Quinazoline Compounds

ABSTRACT

Described herein are compounds of Formula (I) and tautomers and pharmaceutical salts thereof, compositions and formulations containing such compounds, and methods of using and making such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 16/718,311, filed Dec.18, 2019, which is a continuation of U.S. Ser. No. 16/239,578, filedJan. 4, 2019, now issued U.S. Pat. No. 10,548,898, which is acontinuation of U.S. Ser. No. 15/634,527, filed Jun. 27, 2017, nowissued U.S. Pat. No. 10,206,926, which is a continuation of U.S. Ser.No. 14/998,042, filed Dec. 23, 2015, now issued U.S. Pat. No. 9,730,936,which claims priority benefit to U.S. Application Ser. No. 62/096,748,filed Dec. 24, 2014, the disclosure of which are herein incorporated byreference in their entirety.

BACKGROUND

While progress has been made in treating HIV and AIDS, HIV infectionremains a global health concern. As part of such treatments,non-nucleoside reverse transcriptase inhibitors (NNRTIs) have often beenemployed, particularly as part of highly active antiretroviral therapy(HAART) treatment regimens. Though potent, drawbacks exist for many ofthe known NNRTIs as their use has been associated with mutations in theHIV virus that may result in drug resistance. As such, there remains aneed for further development of potent NNTRIs.

Described herein are compounds of Formula (I) and pharmaceuticallyacceptable salts thereof, compositions and formulations containing suchcompounds, or pharmaceutically acceptable salts thereof, and methods ofusing and making such compounds, or pharmaceutically acceptable saltsthereof.

SUMMARY

In certain embodiments, the present disclosure relates to compounds ofFormula (I) or a tautomer thereof,

wherein

Q is

X¹, X², and X³ are each independently N or C(R¹¹), provided that, atmost 2 of X¹, X², and X³ are N;

R¹ is —H, —CN, —OR^(a), —C(O)OR^(a), halogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl, or C₁₋₆heteroalkyl, wherein each C₁₋₆alkyl,C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1,2, 3, 4, or 5 R¹² groups, which may be same or different;

R² is —H, —CN, —OR^(a), —NR^(a)R^(b), —C(O)OR^(a), halogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl, or C₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl,C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1,2, 3, 4, or 5 R¹² groups, which may be same or different;

R³ is —H, —OR^(a), —SR^(a), —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), C₁₋₆alkyl,C₃₋₁₀cycloalkyl, or C₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl,C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1,2, 3, 4, or 5 R¹² groups, which may be same or different; R⁴ is —H,—OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —CH₂C(O)NR^(a)R^(b), C₁₋₆alkyl, C₃₋₁₀cycloalkyl, orC₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁵ is —H, —OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —CH₂C(O)NR^(a)R^(b), C₁₋₆alkyl, C₃₋₁₀cycloalkyl, orC₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁶ is —H, —OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —CH₂C(O)NR^(a)R^(b), C₁₋₆alkyl, C₃₋₁₀cycloalkyl, orC₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁷ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, halogen, —OR^(a),—CN, or —NO₂, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁸ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, halogen, —OR^(a),—CN, or —NO₂, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁹ is —H, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl, wherein each C₁₋₆alkyl andC₃₋₁₀cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹²groups, which may be same or different;

R¹⁰ is —H, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl, wherein each C₁₋₆alkyl andC₃₋₁₀cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹²groups, which may be same or different;

each R¹¹ is independently —H, —CN, —OR^(a), —C(O)OR^(a), halogen,C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or C₁₋₆heteroalkyl, which may be same ordifferent, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkylis optionally substituted with 1, 2, 3, 4, or 5 R¹² groups, which may besame or different;

each R¹² is independently C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl,5-10 membered heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl,halogen, —OR^(a), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂F,—S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂; wherein eachC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, and 5-10 memberedheterocyclyl is optionally substituted with 1, 2, 3, 4, or 5substituents selected from halogen, —OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)C(O)OR^(b), —SR^(a),—S(O)₁₋₂R^(a), —S(O)₂F, —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN,and —NO₂, groups, which may be same or different;

each R^(a) and R^(b) is independently —H, —NH₂, C₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 5-10 membered heterocyclyl, C₆₋₁₀aryl,or 5-10 membered heteroaryl, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₁₋₆heteroalkyl, 5-10 membered heterocyclyl, C₆₋₁₀aryl, and 5-10membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R¹³groups, which may be same or different; or R^(a) and R^(b) together withthe atoms to which they are attached form a 5-10 membered heterocycle;and

each R¹³ is independently —CN, halogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₁₋₆heteroalkyl, or 5-10 membered heterocyclyl;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the current disclosure relates to apharmaceutical composition comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

In certain embodiments, the current disclosure relates to an article ofmanufacture comprising a unit dosage of a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In certain embodiments, the current disclosure relates to a method ofinhibiting reverse transcriptase in a subject in need thereof,comprising administering a compound of Formula (I), or apharmaceutically acceptable salt thereof, to the subject.

In certain embodiments, the current disclosure relates to a method fortreating or preventing an HIV infection in a subject in need thereof,comprising administering to the subject a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In certain embodiments, the current disclosure relates to a method forpreventing an HIV infection in a subject, comprising administering tothe subject a compound of Formula (I), or a pharmaceutically acceptablesalt thereof. In certain embodiments, the subject is at risk ofcontracting the HIV virus, such as a subject who has one or more riskfactors known to be associated with contracting the HIV virus.

In certain embodiments, the current disclosure relates to a method fortreating or preventing an HIV infection in a subject in need thereof,comprising administering to the subject a compound of Formula (I), or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more additional therapeuticagents.

In certain embodiments, the current disclosure relates to a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, for use inmedical therapy.

In certain embodiments, the current disclosure relates to a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, for use intreating or preventing an HIV virus infection in a subject.

In certain embodiments, the current disclosure relates to the use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for the manufacture of a medicament for treating or preventing an HIVvirus infection in a subject.

Additional embodiments of the present disclosure are disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows results of resistance profile against HIV-1 RT (ReverseTranscriptase) mutants of certain compounds.

DETAILED DESCRIPTION

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. A dash at the front or end of a chemical group is a matter ofconvenience to indicate the point of attachment to a parent moiety;chemical groups may be depicted with or without one or more dasheswithout losing their ordinary meaning. A wavy line drawn through a linein a chemical structure or a dashed line drawn through a line in achemical structure indicates a point of attachment of a group. A dashedline within a chemical structure indicates an optional bond. A prefixsuch as “C_(u-v)” or (C_(u)-C_(v)) indicates that the following grouphas from u to v carbon atoms. For example, “C₁₋₆alkyl” indicates thatthe alkyl group has from 1 to 6 carbon atoms.

When trade names are used herein, it is intended to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

As used herein and in the appended claims, the singular forms “a” and“an”, and “the” include plural referents unless the context clearlydictates otherwise. Thus, e.g., reference to “the compound” includes aplurality of such compounds and reference to “the assay” includesreference to one or more assays, and so forth.

“Alkyl” as used herein is a linear or branched saturated monovalenthydrocarbon. For example, an alkyl group can have 1 to 20 carbon atoms(i.e., (C₁₋₂₀)alkyl) or an alkyl group can have 1 to 10 carbon atoms(i.e., (C₁₋₁₀)alkyl), or an alkyl group can have 1 to 8 carbon atoms(i.e., (C₁₋₈)alkyl), or 1 to 6 carbon atoms (i.e., (C₁₋₆ alkyl), or 1 to4 carbon atoms (i.e., (C₁₋₄)alkyl). Examples of alkyl groups include,but are not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-I-propyl (i-Bu,i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 annular carbon atoms, 6 to 14 annular carbon atoms, or6 to 12 annular carbon atoms. Aryl includes a phenyl radical. Aryl alsoincludes multiple condensed ring systems (e.g., ring systems comprising2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least onering is aromatic and wherein the other rings may be aromatic or notaromatic (i.e., carbocycle). Such multiple condensed ring systems areoptionally substituted with one or more (e.g., 1, 2 or 3) oxo groups onany carbocycle portion of the multiple condensed ring system. The ringsof the multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis also to be understood that when reference is made to a certainatom-range membered aryl (e.g., 6-12 membered aryl), the atom range isfor the total ring (annular) atoms of the aryl. For example, a6-membered aryl would include phenyl and a 10-membered aryl wouldinclude naphthyl and 1, 2, 3, 4-tetrahydronaphthyl. Non-limitingexamples of aryl groups include, but are not limited to, phenyl,indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and thelike.

“Arylalkyl” refers to an alkyl radical as defined herein in which one ofthe hydrogen atoms bonded to a carbon atom is replaced with an arylradical as described herein (i.e., an aryl-alkyl-moiety). The alkylgroup of the “arylalkyl” includes alkyl groups that are 1 to 6 carbonatoms (i.e. aryl(C₁-C₆)alkyl). Arylalkyl groups include, but are notlimited to, benzyl, 2-phenylethan-1-yl, 1-phenylpropan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl and the like.

“Boronic acid” refers to the group —B(OH)₂.

“Boronic acid ester” refers to an ester derivative of a boronic acidcompound. Suitable boronic acid ester derivatives include those of theformula —B(OR)₂ where each R is independently alkyl, aryl, arylalkyl,heteroalkyl, or heteroaryl. Additionally, the two R groups of —B(OR)₂may be taken together to form a cyclic ester, e.g. having the structure

where each R may be the same or different. Examples of boronic acidester include boronic acid pinacol ester and boronic acid catecholester.

“Cycloalkyl” refers to a single saturated or partially unsaturated allcarbon ring having 3 to 20 annular carbon atoms (i.e., C₃-C₂₀cycloalkyl), for example from 3 to 12 annular atoms, for example from 3to 10 annular atoms. The term “cycloalkyl” also includes multiplecondensed, saturated and partially unsaturated all carbon ring systems(e.g., ring systems comprising 2, 3 or 4 carbocyclic rings).Accordingly, cycloalkyl includes multicyclic carbocycles such as abicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12annular carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic andtetracyclic carbocycles with up to about 20 annular carbon atoms). Therings of a multiple condensed ring system can be connected to each othervia fused, spiro and bridged bonds when allowed by valency requirements.Non-limiting examples of monocyclic cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and1-cyclohex-3-enyl.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

The term “heteroalkyl” as used herein refers to an alkyl as definedherein, wherein one or more of the carbon atoms of the alkyl arereplaced by an O, S, or NR^(q), (or if the carbon atom being replaced isa terminal carbon with an OH, SH or N(R^(q))₂) wherein each R^(q) isindependently H or (C₁-C₆)alkyl. For example, (C₁-C₈)heteroalkyl intendsa heteroalkyl wherein one or more carbon atoms of a C₁-C₈ alkyl isreplaced by a heteroatom (e.g., O, S, NR^(q), OH, SH or N(R^(q))₂),which may the same or different. Examples of heteroalkyls include butare not limited to methoxymethyl, ethoxymethyl, methoxy, 2-hydroxyethyland N,N′-dimethylpropylamine. A heteroatom of a heteroalkyl mayoptionally be oxidized or alkylated. A heteroatom may be placed at anyinterior position of the heteroalkyl group or at a position at which thegroup is attached to the remainder of the molecule. Examples include,but are not limited to, —CH₂OCH₃, —CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)—CH₃,—CH₂SCH₂CH₃, —S(O)CH₃, —CH₂CH₂S(O)₂CH₃, —CH₂CH₂OCH₃, —CHCHN(CH₃)CH₃,—CH₂NHOCH₃ and —CH₂OC(CH₃)₃.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; the term also includes multiple condensed ring systems that haveat least one such aromatic ring, which multiple condensed ring systemsare further described below. Thus, the term includes single aromaticrings of from about 1 to 6 annular carbon atoms and about 1-4 annularheteroatoms selected from the group consisting of oxygen, nitrogen andsulfur in the rings. The sulfur and nitrogen atoms may also be presentin an oxidized form provided the ring is aromatic. Such rings includebut are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. The termalso includes multiple condensed ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) wherein a heteroaryl group, as definedabove, can be condensed with one or more rings selected from heteroaryls(to form for example a naphthyridinyl such as 1,8-naphthyridinyl),heterocycloalkyls, (to form for example a1,2,3,4-tetrahydronaphthyridinyl such as 1, 2, 3,4-tetrahydro-1,8-naphthyridinyl), cycloalkyls (to form for example5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) toform the multiple condensed ring system. Thus, a heteroaryl (a singlearomatic ring or multiple condensed ring system) has about 1-20 annularcarbon atoms and about 1-6 annular heteroatoms. Such multiple condensedring systems may be optionally substituted with one or more (e.g., 1, 2,3 or 4) oxo groups on the carbocycle or heterocycle portions of thecondensed ring. The rings of the multiple condensed ring system can beconnected to each other via fused, spiro and bridged bonds when allowedby valency requirements. It is to be understood that the individualrings of the multiple condensed ring system may be connected in anyorder relative to one another. It is also to be understood that thepoint of attachment of a multiple condensed ring system (as definedabove for a heteroaryl) can be at any position of the multiple condensedring system including a heteroaryl, heterocycle, aryl or carbocycleportion of the multiple condensed ring system and at any suitable atomof the multiple condensed ring system including a carbon atom andheteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are notlimited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl,pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl,oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl,benzoxazolyl, indazolyl, quinoxalyl, quinazolyl,5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl andthianaphthenyl.

“Heterocycloalkyl” or “heterocyclyl” as used herein refers to a singlesaturated or partially unsaturated non-aromatic ring or a non-aromaticmultiple ring system that has at least one heteroatom in the ring (atleast one annular heteroatom selected from oxygen, nitrogen, andsulfur). Unless otherwise specified, a heterocycloalkyl group has from 5to about 20 annular atoms, for example from 5 to 14 annular atoms, forexample from 5 to 10 annular atoms. Thus, the term includes singlesaturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-memberedrings) having from about 1 to 6 annular carbon atoms and from about 1 to3 annular heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur in the ring. The term also includes single saturatedor partially unsaturated rings (e.g., 5, 6, 7, 8, 9, or 10-memberedrings) having from about 4 to 9 annular carbon atoms and from about 1 to3 annular heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur in the ring. The rings of the multiple condensedring system can be connected to each other via fused, spiro and bridgedbonds when allowed by valency requirements. Heterocycloalkyl groupsinclude, but are not limited to, azetidine, aziridine, imidazolidine,imino-oxoimidazolidine, morpholine, oxirane (epoxide), oxetane,piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine,pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine,tetrahydropyridine, quinuclidine, N-bromopyrrolidine,N-chloropiperidine, and the like.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Oxo” refers to a double-bonded oxygen (═O). In compounds where an oxogroup is bound to an sp² nitrogen atom, an N-oxide is indicated.

It is understood that combinations of chemical groups may be used andwill be recognized by persons of ordinary skill in the art. Forinstance, the group “hydroxyalkyl” would refer to a hydroxyl groupattached to an alkyl group.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstance may but need not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not.

“Tautomers” as used herein refers to isomers of a compound that differfrom each other in the position of a proton and/or in electronicdistribution. Thus, both proton migration tautomers and valencetautomers are intended and described and it is understood that more thantwo tautomers may exist for a given compound. Examples of tautomersinclude, but are not limited to, enol-keto tautomers:

imine-enamine tautomers:

lactam-lactim tautomers:

amide-imidic acid tautomers:

amino-imine tautomers:

and tautomeric forms of heteroaryl groups containing a ring atomattached to both a ring —NH— moiety and a ring ═N— moiety such aspresent in pyrazoles, imidazoles, benzimidazoles, triazoles andtetrazoles (see, e.g., Smith, March's Advanced Organic Chemistry (5^(th)ed.), pp. 1218-1223, Wiley-Interscience, 2001; Katritzky A. and ElgueroJ, et al., The Tautomerism of Heterocycles, Academic Press (1976)).

“Pharmaceutically acceptable” refers to compounds, salts, compositions,dosage forms and other materials which are useful in preparing apharmaceutical composition that is suitable for veterinary or humanpharmaceutical use.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses (or can be convertedto a form that possesses) the desired pharmacological activity of theparent compound. Such salts include acid addition salts formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like; or formed with organicacids such as acetic acid, benzenesulfonic acid, benzoic acid,camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid,glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonicacid, mandelic acid, methanesulfonic acid, 2-napththalenesulfonic acid,oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid,tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and thelike, and salts formed when an acidic proton present in the parentcompound is replaced by either a metal ion, e.g., an alkali metal ion(e.g. a sodium or potassium), an alkaline earth ion (e.g. calcium ormagnesium), or an aluminum ion; or coordinates with an organic base suchas diethanolamine, triethanolamine, N-methylglucamine and the like. Alsoincluded in this definition are ammonium and substituted or quaternizedammonium salts. Representative non-limiting lists of pharmaceuticallyacceptable salts can be found in S. M. Berge et al., J. Pharma Sci.,66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy,R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins,Philadelphia, Pa., (2005), at p. 732, Table 38-5, both of which arehereby incorporated by reference herein.

“Subject” and “subjects” refers to humans, domestic animals (e.g., dogsand cats), farm animals (e.g., cattle, horses, sheep, goats and pigs),laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs,rabbits, dogs, and monkeys), and the like.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results. For purposes of the present disclosure,beneficial or desired results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomand/or preventing a worsening of a symptom associated with a disease orcondition. In one embodiment, “treatment” or “treating” includes one ormore of the following: a) inhibiting the disease or condition (e.g.,decreasing one or more symptoms resulting from the disease or condition,and/or diminishing the extent of the disease or condition); b) slowingor arresting the development of one or more symptoms associated with thedisease or condition (e.g., stabilizing the disease or condition,delaying the worsening or progression of the disease or condition); andc) relieving the disease or condition, e.g., causing the regression ofclinical symptoms, ameliorating the disease state, delaying theprogression of the disease, increasing the quality of life, and/orprolonging survival.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of AIDS is a method that reduces the probability ofdisease development in a given time frame and/or reduces extent of thedisease in a given time frame, when compared to not using the method.Such comparisons may be based on clinical studies, using a statisticallysignificant number of subjects. For example, the development of AIDS canbe detected using known methods, such as confirming an individual's HIV⁺status and assessing the individual's T-cell count or other indicationof AIDS development, such as extreme fatigue, weight loss, persistentdiarrhea, high fever, swollen lymph nodes in the neck, armpits or groin,or presence of an opportunistic condition that is known to be associatedwith AIDS (e.g., a condition that is generally not present inindividuals with functioning immune systems but does occur in AIDSpatients). Development may also refer to disease progression that may beinitially undetectable and includes occurrence, recurrence and onset.

As used herein, “prevention” or “preventing” refers to a regimen thatprotects against the onset of the disease or disorder such that theclinical symptoms of the disease do not develop. Thus, “prevention”relates to administration of a therapy (e.g., administration of atherapeutic substance) to a subject before signs of the disease aredetectable in the subject (e.g., administration of a therapeuticsubstance to an subject in the absence of detectable infectious agent(e.g., virus) in the subject). The subject may be an individual at riskof developing the disease or disorder, such as an individual who has oneor more risk factors known to be associated with development or onset ofthe disease or disorder. Thus, the term “preventing HIV infection”refers to administering to a subject who does not have a detectable HIVinfection an anti-HIV therapeutic substance. It is understood that thesubject for anti-HIV preventative therapy may be an individual at riskof contracting the HIV virus.

As used herein, an “at risk” individual is an individual who is at riskof developing a condition to be treated. An individual “at risk” may ormay not have detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment of methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). For example, individuals at risk for AIDSare those having HIV.

As used herein, the term “effective amount” refers to an amount that iseffective to elicit the desired biological or medical response,including the amount of a compound that, when administered to a subjectfor treating a disease, is sufficient to effect such treatment for thedisease. The effective amount will vary depending on the compound, thedisease, and its severity and the age, weight, etc., of the subject tobe treated. The effective amount can include a range of amounts. As isunderstood in the art, an effective amount may be in one or more doses,i.e., a single dose or multiple doses may be required to achieve thedesired treatment endpoint. An effective amount may be considered in thecontext of administering one or more therapeutic agents, and a singleagent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any co-administeredcompounds may optionally be lowered due to the combined action (e.g.,additive or synergistic effects) of the compounds.

Except as expressly defined otherwise, the present disclosure includesall tautomers of compounds detailed herein, even if only one tautomer isexpressly represented (e.g., both tautomeric forms are intended anddescribed by the presentation of one tautomeric form where a pair of twotautomers may exist). For example, if reference is made to a compoundcontaining a lactam (e.g., by structure or chemical name), it isunderstood that the corresponding lactim tautomer is included by thisdisclosure and described the same as if the lactim were expresslyrecited either alone or together with the lactam. Where more than twotautomers may exist, the present disclosure includes all such tautuomerseven if only a single tautomeric form is depicted by chemical nameand/or structure.

Compositions detailed herein may comprise a compound of the presentdisclosure in a racemic or non-racemic mixture of stereoisomers or maycomprise a compound of the present disclosure as a substantially pureisomer. Stereoisomers include enantiomers and diastereomers. Thecompounds may exist in stereoisomeric form if they possess one or moreasymmetric centers or a double bond with asymmetric substitution and,therefore, can be produced as individual stereoisomers or as mixtures.Unless otherwise indicated, the description is intended to includeindividual stereoisomers as well as mixtures. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see, e.g., Chapter 4 of Advanced OrganicChemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

It is understood by one skilled in the art that this disclosure alsoincludes any compound disclosed herein that may be enriched at any orall atoms above naturally occurring isotopic ratios with one or moreisotopes such as, but not limited to, deuterium (²H or D).

Disclosed are also compounds in which from 1 to n hydrogen atomsattached to a carbon atom may be replaced by a deuterium atom or D, inwhich n is the number of hydrogen atoms in the molecule. As known in theart, the deuterium atom is a non-radioactive isotope of the hydrogenatom. Such compounds may increase resistance to metabolism, and thus maybe useful for increasing the half-life of the compounds whenadministered to a mammal. See, e.g., Foster, “Deuterium Isotope Effectsin Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527(1984). Such compounds are synthesized by means well known in the art,for example by employing starting materials in which one or morehydrogen atoms have been replaced by deuterium.

Compounds of a given formula described herein encompasses the compounddisclosed and all pharmaceutically acceptable salts, esters,stereoisomers, tautomers, prodrugs, solvates, and deuterated formsthereof, unless otherwise specified.

Depending on the particular substituents, the compounds of Formula I mayexist in tautomeric forms. It is understood that two or more tautomericforms may exist for a given compound structure. For example, a compoundof Formula I (where R³ is —OH) may exist in at least the followingtautomeric forms:

As is understood by those of skill in the art, various other tautomericforms may exist and are intended to be encompassed by the compounds ofFormula I. Some descriptions herein expressly refer to “tautomersthereof” but it is understood that, even in the absence of suchlanguage, tautomers are intended and described. Further, it isunderstood that the compounds of Formula I may shift between varioustautomeric forms or exist in various ratios of each form based on theparticular environment of the compound.

The compounds disclosed herein may contain chiral centers, which may beeither of the (R) or (S) configuration, or which may comprise a mixturethereof. Accordingly, the present disclosure includes stereoisomers ofthe compounds described herein, where applicable, either individually oradmixed in any proportions. Stereoisomers may include, but are notlimited to, enantiomers, diastereomers, racemic mixtures, andcombinations thereof. Such stereoisomers can be prepared and separatedusing conventional techniques, either by reacting enantiomeric startingmaterials, or by separating isomers of compounds of the presentdisclosure.

The compounds of the present disclosure may be compounds according toFormula (I) with one or more chiral centers, which may be either of the(R) or (S) configuration, or which may comprise a mixture thereof.

The present disclosure includes both racemic mixtures of a compound offormula I and isolated isomers of Formula (I) or any variation thereof.Where more than one chiral center is present in a compound of thepresent disclosure, some, none, or all of the chiral centers may beenantiomerically enriched. Thus, mixtures of a compound of Formula (I)may be racemic with respect to one or more chiral centers and/orenantiomerically enriched with respect to one or more chiral centers.

The present disclosure relates to a compound of formula (I)

wherein

Q is

X¹, X², and X³ are each independently N or C(R¹¹), provided that, atmost 2 of X¹, X², and X³ are N;

R¹ is —H, —CN, —OR^(a), —C(O)OR^(a), halogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl, or C₁₋₆heteroalkyl, wherein each C₁₋₆alkyl,C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1,2, 3, 4, or 5 R¹² groups, which may be same or different;

R² is —H, —CN, —OR^(a), —NR^(a)R^(b), —C(O)OR^(a), halogen, C₁₋₆alkyl,C₃₋₁₀cycloalkyl, or C₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl,C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1,2, 3, 4, or 5 R¹² groups, which may be same or different;

R³ is —H, —OR^(a), —SR^(a), —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), C₁₋₆alkyl,C₃₋₁₀cycloalkyl, or C₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl,C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1,2, 3, 4, or 5 R¹² groups, which may be same or different;

R⁴ is —H, —OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —CH₂C(O)NR^(a)R^(b), C₁₋₆alkyl, C₃₋₁₀cycloalkyl, orC₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁵ is —H, —OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —CH₂C(O)NR^(a)R^(b), C₁₋₆alkyl, C₃₋₁₀cycloalkyl, orC₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁶ is —H, —OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —CH₂C(O)NR^(a)R^(b), C₁₋₆alkyl, C₃₋₁₀cycloalkyl, orC₁₋₆ heteroalkyl, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁷ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, halogen, —OR^(a),—CN, or —NO₂, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁸ is C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, halogen, —OR^(a),—CN, or —NO₂, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R⁹ is —H, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl, wherein each C₁₋₆alkyl andC₃₋₁₀cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹²groups, which may be same or different;

R¹⁰ is —H, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl, wherein each C₁₋₆alkyl andC₃₋₁₀cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹²groups, which may be same or different;

each R¹¹ is independently —H, —CN, —OR^(a), —C(O)OR^(a), halogen,C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or C₁₋₆heteroalkyl, which may be same ordifferent, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkylis optionally substituted with 1, 2, 3, 4, or 5 R¹² groups, which may besame or different;

each R¹² is independently C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl,5-10 membered heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl,halogen, —OR^(a), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —N^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂F,—S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂; wherein eachC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, and 5-10 memberedheterocyclyl is optionally substituted with 1, 2, 3, 4, or 5substituents selected from halogen, —OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)C(O)OR^(b), —SR^(a),—S(O)₁₋₂R^(a), —S(O)₂F, —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN,and —NO₂, groups, which may be same or different;

each R^(a) and R^(b) is independently —H, —NH₂, C₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 5-10 membered heterocyclyl, C₆₋₁₀aryl,or 5-10 membered heteroaryl, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₁₋₆heteroalkyl, 5-10 membered heterocyclyl, C₆₋₁₀aryl, and 5-10membered heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 R¹³groups, which may be same or different; or R^(a) and R^(b) together withthe atoms to which they are attached form a 5-10 membered heterocycle;and

each R¹³ is independently —CN, halogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₁₋₆heteroalkyl, or 5-10 membered heterocyclyl;

or a tautomer or a pharmaceutically acceptable salt thereof.

In certain embodiments in formula (I), R² is —H, —CN, —OR^(a), orC₁₋₆alkyl.

In certain embodiments in formula (I), R² is —CN.

In one variation, the present disclosure relates to compounds of formula(II), which are compounds of formula (I):

wherein

Q is

X¹, X², and X³ are each independently N or C(R¹¹), provided that, atmost 2 of X¹, X², and X³ are N;

R¹ is —H, —CN, —OR^(a), —C(O)OR^(a), halogen, or C₁₋₆alkyl, whereinC₁₋₆alkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹² groups,which may be same or different;

R³ is —H, —OR^(a), —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), C₁₋₆alkyl, orC₁₋₆heteroalkyl, wherein each C₁₋₆alkyl and C₁₋₆heteroalkyl isoptionally substituted with 1, 2, 3, 4, or 5 R¹² groups, which may besame or different;

R⁴ is —H, —OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b), C₁₋₆alkyl, or C₁₋₆heteroalkyl, wherein each C₁₋₆alkyl and C₁₋₆ heteroalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 R¹² groups, which may be same ordifferent;

R⁵ is —H, —OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b), C₁₋₆alkyl, or C₁₋₆heteroalkyl, wherein each C₁₋₆alkyl and C₁₋₆ heteroalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 R¹² groups, which may be same ordifferent;

R⁶ is —H, —OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b), C₁₋₆alkyl, or C₁₋₆heteroalkyl, wherein each C₁₋₆alkyl and C₁₋₆ heteroalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 R¹² groups, which may be same ordifferent;

R⁷ is C₁₋₆alkyl, C₁₋₆heteroalkyl, halogen, —OR^(a), —CN, or —NO₂,wherein each C₁₋₆alkyl is optionally substituted with 1, 2, 3, 4, or 5R¹² groups, which may be same or different;

R⁸ is C₁₋₆alkyl, C₁₋₆heteroalkyl, halogen, —OR^(a), —CN, or —NO₂,wherein each C₁₋₆alkyl is optionally substituted with 1, 2, 3, 4, or 5R¹² groups, which may be same or different;

R⁹ is —H or C₁₋₆alkyl, wherein C₁₋₆alkyl is optionally substituted with1, 2, 3, 4, or 5 R¹² groups, which may be same or different;

R¹⁰ is —H or C₁₋₆alkyl wherein C₁₋₆alkyl is optionally substituted with1, 2, 3, 4, or 5 R¹² groups, which may be same or different;

each R¹¹ is independently —H, —CN, —OR^(a), —C(O)OR^(a), halogen, orC₁₋₆alkyl, which may be same or different, wherein C₁₋₆alkyl isoptionally substituted with 1, 2, 3, 4, or 5 R¹² groups, which may besame or different;

each R¹² is independently C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl,5-10 membered heterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl,halogen, —OR^(a), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —N^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂F,—S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂; wherein eachC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, and 5-10 memberedheterocyclyl is optionally substituted with 1, 2, 3, 4, or 5substituents selected from halogen, —OR^(a), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b), —NR^(a)C(O)OR^(b), —SR^(a),—S(O)₁₋₂R^(a), —S(O)₂F, —S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN,and —NO₂, groups, which may be same or different;

each R^(a) and R^(b) is independently —H, C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₁₋₆heteroalkyl, 5-10 membered heterocyclyl, C₆₋₁₀aryl, or 5-10 memberedheteroaryl, wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl,5-10 membered heterocyclyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl isoptionally substituted with 1, 2, 3, 4, or 5 R¹³ groups, which may besame or different; or R^(a) and R^(b) together with the atoms to whichthey are attached form a 5-10 membered heterocycle; and

each R¹³ is independently —CN, halogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl,C₁₋₆heteroalkyl, or 5-10 membered heterocyclyl,

or a tautomer or a pharmaceutically acceptable salt thereof.

In certain embodiments in formula (I) and (II), Q is

In certain embodiments in formula (I) and (II), Q is

In certain embodiments in formula (I) and (II), X¹, X², and X³ are eachindependently N or C(R¹¹), wherein 2 of X¹, X², and X³ are N. In certainembodiments, X¹, X², and X³ are each independently N or C(R¹¹), whereinone of X¹, X², and X³ is N. In certain embodiments, X¹, X², and X³ areeach independently N or C(R¹¹), wherein none of X¹, X², and X³ is N.

In certain embodiments in formula (I) and (II), X¹, X², and X³ are eachC(R¹¹). In certain embodiments in formula (I) and (II), X¹, X², and X³are each CH. In certain embodiments, X¹ is N; X² is C(R¹¹); and X³ isC(R¹¹). In certain embodiments, X¹ is N; X² is CH; and X³ is CH.

In certain embodiments in formula (I) and (II), X¹ is N; X² is N; and X³is C(R¹¹). In certain embodiments, X¹ is N; X² is C(R¹¹); and X³ is N.In certain embodiments, X¹ is C(R¹¹); X² is N; and X³ is C(R¹¹).

In certain embodiments in formula (I) and (II), R¹ is —H or C₁₋₆alkyl.In certain embodiments, R¹ is —H. In certain embodiments, R¹ isC₁₋₆alkyl. In certain embodiments, R¹ is methyl.

In certain embodiments in formula (I) and (II), X¹, X², and X³ areC(R¹¹); each R¹¹ are independently selected from —H, —CN, —OR^(a),halogen, and C₁₋₆alkyl; and R¹ is selected from —H, —CN, —OR^(a),halogen, and C₁₋₆alkyl. In certain embodiments, X¹, X², and X³ areC(R¹¹); each R¹¹ are —H; and R¹ is —H.

In certain embodiments in formula (I) and (II), X¹ is N; X² is C(R¹¹);and X³ is C(R¹¹); each R¹¹ are independently selected from —H, —CN,—OR^(a), halogen, and C₁₋₆alkyl; and R¹ is selected from —H, —CN,—OR^(a), halogen, and C₁₋₆alkyl. In certain embodiments, X¹ is N; X² isC(R¹¹); and X³ is C(R¹¹); each R¹¹ are —H; and R¹ is selected from —Hand C₁₋₆alkyl. In certain embodiments, X¹ is N; X² is C(R¹¹); and X³ isC(R¹¹); each R¹¹ are —H; and R¹ is —H.

In certain embodiments in formula (I) and (II),

of formula (I) or (II) is selected from

In certain embodiments in formula (I) and (II),

of formula (I) or (II) is

In certain embodiments,

of formula (I) or (II) is

In certain embodiments,

of formula (I) or (II) is

In certain embodiments in formula (I) and (II), R³ is —H, —OR^(a),—NR^(a)R^(b), —NHC(O)NR^(a)R^(b), C₁₋₆alkyl, or C₁₋₆ heteroalkyl. Incertain embodiments, R³ is —H, —OR^(a), —NR^(a)R^(b), or—NHC(O)NR^(a)R^(b).

In certain embodiments in formula (I) and (II), R³ is —NR^(a)R^(b) or—OR^(a). In certain embodiments, R³ is —NH₂ or —OH.

In certain embodiments, R³ is —NR^(a)R^(b). In certain embodiments, R³is —NR^(a)R^(b), wherein each R^(a) and R^(b) is independently —H orC₁₋₆alkyl, wherein the C₁₋₆alkyl is optionally substituted with 1, 2, 3,4, or 5 R¹³ groups. In certain embodiments, R³ is —NR^(a)R^(b), whereineach R^(a) and R^(b) is independently —H or C₁₋₆alkyl. In certainembodiments, R³ is —NR^(a)R^(b), wherein each R^(a) and R^(b) isindependently —H, methyl, butyl, or cyclopropylmethyl. In certainembodiments, R³ is —NH₂.

In certain embodiments in formula (I) and (II), R³ is —OR^(a). Incertain embodiments, R³ is —OH.

In certain embodiments in formula (I) and (II), R³ is —H. In certainembodiments, R³ is —NHC(O)NR^(a)R^(b). In certain embodiments, R³ is—NHC(O)NH₂.

In certain embodiments in formula (I) and (II), R⁴ is —H, —OR^(a),halogen, —NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), or C₁₋₆alkyl. Incertain embodiments, R⁴ is —H or —OR^(a).

In certain embodiments in formula (I) and (II), R⁵ is —H, —OR^(a),halogen, —NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), or C₁₋₆alkyl. Incertain embodiments, R⁵ is —H, —OR^(a), halogen, —NO₂, —CN,—NR^(a)R^(b), or C₁₋₆alkyl.

In certain embodiments in formula (I) and (II), R⁶ is —H, —OR^(a),halogen, —NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), or C₁₋₆alkyl. Incertain embodiments in formula (I) and (II), R⁶ is —H.

In certain embodiments in formula (I) and (II), two of R⁴, R⁵, and R⁶are —H and one of R⁴, R⁵, and R⁶ is —H, —OR^(a), halogen, —NO₂, —CN,—NR^(a)R^(b), —NHC(O)NR^(a)R^(b), or C₁₋₆alkyl. In certain embodiments,two of R⁴, R⁵, and R⁶ are —H and one of R⁴, R⁵, and R⁶ is —H, —OR^(a),halogen, —NO₂, —NR^(a)R^(b), or C₁₋₆alkyl. In certain embodiments, twoof R⁴, R⁵, and R⁶ are —H and one of R⁴, R⁵, and R⁶ is —H, —OCH₃,halogen, —NO₂, —NH₂, or methyl.

In certain embodiments in formula (I) and (II), R⁴, R⁵, and R⁶ are —H.

In certain embodiments in formula (I) and (II), R⁷ is C₁₋₆alkyl,C₁₋₆heteroalkyl, halogen, —OR^(a), —CN, or —NO₂. In certain embodiments,R⁷ is C₁₋₆alkyl, halogen, or —OR^(a).

In certain embodiments in formula (I) and (II), R⁸ is C₁₋₆alkyl,C₁₋₆heteroalkyl, halogen, —OR^(a), —CN, or —NO₂. In certain embodiments,R⁸ is C₁₋₆alkyl, halogen, or —OR^(a).

In certain embodiments in formula (I) and (II), R⁷ and R⁸ are the sameand are selected from C₁₋₆alkyl, C₁₋₆heteroalkyl, halogen, —OR^(a), —CN,and —NO₂. In certain embodiments, R⁷ and R⁸ are the same and areselected from C₁₋₆alkyl, halogen, or —OR^(a).

In certain embodiments in formula (I) and (II), R⁷ and R⁸ are C₁₋₆alkyl.In certain embodiments, R⁷ and R⁸ are methyl.

In certain embodiments in formula (I) and (II), R⁷ and R⁸ are —OR^(a).In certain embodiments, R⁷ and R⁸ are —OCH₃.

In certain embodiments in formula (I) and (II), R⁷ and R⁸ are halogen.In certain embodiments, R⁷ and R⁸ are fluoro.

In certain embodiments in formula (I) and (II), R⁹ is —H or C₁₋₆alkyl.In certain embodiments, R⁹ is —H or methyl.

In certain embodiments in formula (I) and (II), R¹⁰ is —H or C₁₋₆alkyl.In certain embodiments in formula (I) and (II), R¹⁰ is —H or methyl.

In certain embodiments in formula (I) and (II), R⁹ is —H or C₁₋₆alkyl;and R¹⁰ is —H or C₁₋₆alkyl. In certain embodiments, R⁹ is —H or methyl;and R¹⁰ is —H or methyl. In certain embodiments in formula (I) and (II),R⁹ and R¹⁰ are —H.

In certain embodiments in formula (I) and (II), Q is selected from

In certain embodiments in formula (I) and (II), Q is

It is understood that any variable for Q of formula (I) and (II) may becombined with any variable of R³ in formula (I) and (II), the same as ifeach and every combination were specifically and individually listed.For example, in one variation of formula (I) and (II), Q is

and R³ is —NH₂. In another variation, Q is

and R³ is —OH.

It is understood that any variable for R⁷ of formula (I) and (II) may becombined with any variable of R³ in formula (I) and (II), the same as ifeach and every combination were specifically and individually listed.For example, in one variation of formula (I) and (II), R⁷ is methyl andR³ is —NH₂. In another variation, R⁷ is methyl and R³ is —OH.

It is understood that any variable for R⁸ of formula (I) and (II) may becombined with any variable of R³ in formula (I) and (II), the same as ifeach and every combination were specifically and individually listed.For example, in one variation of formula (I) and (II), R⁸ is methyl andR³ is —NH₂. In another variation, R⁸ is methyl and R³ is —OH.

It is understood that any variable for R⁴, R⁵, and R⁶ of formula (I) and(II) may be combined with any variable of R³ in formula (I) and (II),the same as if each and every combination were specifically andindividually listed. For example, in one variation of formula (I) and(II), R⁴, R⁵, and R⁶ are each —H; and R³ is —NH₂. In another variation,R⁴, R⁵, and R⁶ are each —H; and R³ is —OH.

It is understood that any variable for X¹, X², and X³ of formula (I) and(II) may be combined with any variable of R³ in formula (I) and (II),the same as if each and every combination were specifically andindividually listed. For example, in one variation of formula (I) and(II), X¹, X², and X³ are each CH; and R³ is —NH₂. In one variation offormula (I) and (II), X¹ is N; X² is CH; and X³ is CH; and R³ is —NH₂.In another variation, X¹ is N; X² is CH; and X³ is CH; and R³ is —OH. Inanother variation, X¹, X², and X³ are each CH; and R³ is —OH.

It is understood that any variable for R¹ of formula (I) and (II) may becombined with any variable of R³ in formula (I) and (II), the same as ifeach and every combination were specifically and individually listed.For example, in one variation of formula (I) and (II), R¹ is hydrogenand R³ is —NH₂. In another variation, R¹ is hydrogen and R³ is —OH.

In certain embodiments of formula (I) and (II), where R³ is —NH₂, thecompounds may have any one or more of the following structural features:

a) X¹, X², and X³ are each CH;b) R⁷ is methyl;c) R⁸ is methyl;

d) Q is

ande) R⁴, R⁵, and R⁶ are each —H.

In one variation, the compounds conform to at least one of features(a)-(e). In another variation, the compounds conform to two or more (andin certain variations, all) of features (a)-(e). In a particularvariation, the compounds conform to feature (a). In another variation,the compounds conform to features (a), (b), and (c). In anothervariation, the compounds conform to features (a) and (d). In anothervariation, the compounds conform to features (a) and (e).

In certain embodiments of formula (I) and (II), where R³ is —OH, thecompounds may have any one or more of the following structural features:

a) X¹ is N; X² is CH; and X³ is CH;b) R⁷ is methyl;c) R⁸ is methyl;

d) Q is

ande) R⁴, R⁵, and R⁶ are each —H.

In one variation, the compounds conform to at least one of features(a)-(e). In another variation, the compounds conform to two or more (andin certain variations, all) of features (a)-(e). In a particularvariation, the compounds conform to feature (a). In another variation,the compounds conform to features (a), (b), and (c). In anothervariation, the compounds conform to features (a) and (d). In anothervariation, the compounds conform to features (a) and (e).

In certain embodiments of formula (I) and (II), where Q is

the compounds may have any one or more of the following structuralfeatures:a) X¹, X², and X³ are each CH or X¹ is N; X² is CH; and X³ is CH;b) R³ is —NH₂ or —OH;c) R⁷ and R⁸ are methyl;d) R⁴, R⁵, and R⁶ are each —H.

In one variation, the compounds conform to at least one of features(a)-(d). In another variation, the compounds conform to two or more (andin certain variations, all) of features (a)-(d). In a particularvariation, the compounds conform to feature (a). In another variation,the compounds conform to features (a) and (b). In another variation, thecompounds conform to features (a), (b), and (c). In another variation,the compounds conform to features (a), (b), and (d).

The present disclosure relates to the following compounds or apharmaceutically acceptable salt thereof.

Structure Compound ID

1

2

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5

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8

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41

The present disclosure relates to the following compound or a tautomeror a pharmaceutically acceptable salt thereof:

The present disclosure relates to the following compound or apharmaceutically acceptable salt thereof:

and tautomers thereof such as

Pharmaceutical Compositions

Pharmaceutical compositions comprising the compounds disclosed herein,or pharmaceutically acceptable salts thereof, may be prepared withconventional carriers (e.g., inactive ingredient or excipient material)which may be selected in accord with ordinary practice. Tablets maycontain excipients including glidants, fillers, binders and the like.Aqueous compositions may be prepared in sterile form, and when intendedfor delivery by other than oral administration generally may beisotonic. All compositions may optionally contain excipients such asthose set forth in the Rowe et al, Handbook of PharmaceuticalExcipients, 5^(th) edition, American Pharmacists Association, 1986.Excipients can include ascorbic acid and other antioxidants, chelatingagents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. In certain embodiments, the composition relates to a solid dosageform, including a solid oral dosage form. The pH of a composition mayrange from about 3 to about 11, but is ordinarily about 7 to 10.

While it is possible for the active ingredients to be administeredalone, it may be preferable to present them as pharmaceuticalcompositions. The compositions, both for veterinary and for human use,comprise at least one compound of formula (I), together with one or moreacceptable carriers and optionally other therapeutic ingredients. In oneembodiment, the pharmaceutical composition comprises a compound offormula (I), or a tautomer or a pharmaceutically acceptable saltthereof, a pharmaceutically acceptable carrier and one other therapeuticingredient. The carrier(s) are “acceptable” in the sense of beingcompatible with the other ingredients of the composition andphysiologically innocuous to the recipient thereof.

The compositions include those suitable for various administrationroutes, including oral administration. The compositions may convenientlybe presented in unit dosage form and may be prepared by any of themethods well known in the art of pharmacy. Such methods include the stepof bringing into association the active ingredient (e.g., a compound offormula (I) or a pharmaceutical salt thereof) with one or more inactiveingredients (e.g., a carrier, pharmaceutical excipient, etc.). Thecompositions may be prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.Techniques and formulations generally are found in Remington: TheScience and Practice of Pharmacy, 21^(st) Edition, Lippincott Williamsand Wilkins, Philadelphia, Pa., 2006.

Compositions described herein that are suitable for oral administrationmay be presented as discrete units (a unit dosage form) including butnot limited to capsules, cachets or tablets each containing apredetermined amount of the active ingredient.

Pharmaceutical compositions disclosed herein comprise one or morecompounds disclosed herein, or a pharmaceutically acceptable saltthereof, together with one or more pharmaceutically acceptable carriersor excipients and optionally other therapeutic agents. Pharmaceuticalcompositions containing the active ingredient may be in any formsuitable for the intended method of administration. When used for oraluse for example, tablets, troches, lozenges, aqueous or oil suspensions,dispersible powders or granules, emulsions, hard or soft capsules,syrups or elixirs may be prepared. Compositions intended for oral usemay be prepared according to any method known to the art for themanufacture of pharmaceutical compositions and such compositions maycontain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable. These excipients maybe, for example, inert diluents, such as calcium or sodium carbonate,lactose, lactose monohydrate, croscarmellose sodium, povidone, calciumor sodium phosphate; granulating and disintegrating agents, such asmaize starch, or alginic acid; binding agents, such as cellulose,microcrystalline cellulose, starch, gelatin or acacia; and lubricatingagents, such as magnesium stearate, stearic acid or talc. Tablets may beuncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

The amount of active ingredient that may be combined with the inactiveingredients to produce a dosage form may vary depending upon theintended treatment subject and the particular mode of administration.For example, in some embodiments, a dosage form for oral administrationto humans may contain approximately 1 to 1000 mg of active materialformulated with an appropriate and convenient amount of carrier material(e.g., inactive ingredient or excipient material). In certainembodiments, the carrier material varies from about 5 to about 95% ofthe total compositions (weight:weight).

It should be understood that in addition to the ingredients particularlymentioned above the compositions of these embodiments may include otheragents conventional in the art having regard to the type of compositionin question, for example those suitable for oral administration mayinclude flavoring agents.

In certain embodiments, a composition comprising an active ingredientdisclosed herein (a compound of formula (I) or a pharmaceuticallyacceptable salt thereof) in one variation does not contain an agent thataffects the rate at which the active ingredient is metabolized. Thus, itis understood that compositions comprising a compound of formula (I) incertain embodiments do not comprise an agent that would affect (e.g.,slow, hinder or retard) the metabolism of a compound of formula (I) orany other active ingredient administered separately, sequentially orsimultaneously with a compound of formula (I). It is also understoodthat any of the methods, kits, articles of manufacture and the likedetailed herein in certain embodiments do not comprise an agent thatwould affect (e.g., slow, hinder or retard) the metabolism of a compoundof formula (I) or any other active ingredient administered separately,sequentially or simultaneously with a compound of any one of formula(I).

Methods of Use

Disclosed herein is a method of inhibiting an HIV reverse transcriptasein an individual in need thereof, comprising administering a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, to theindividual. In certain embodiments, the individual in need thereof is ahuman who has been infected with HIV. In certain embodiments, theindividual in need thereof is a human who has been infected with HIV butwho has not developed AIDS. In certain embodiments, the individual inneed thereof is an individual at risk for developing AIDS. In certainembodiments, the individual in need thereof is a human who has beeninfected with HIV and who has developed AIDS. In certain embodiments ofthe methods disclosed herein, a compound of Formula (I), or apharmaceutically acceptable salt thereof, is administered to theindividual separately, sequentially or simultaneously with anotheractive ingredient for treating HIV, such as HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and other drugs for treating HIV, andcombinations thereof.

In certain embodiments, a method for treating or preventing an HIV viralinfection in an individual (e.g., a human), comprising administering acompound of formula (I), or a pharmaceutically acceptable salt thereof,to the individual is disclosed.

In certain embodiments, a method for inhibiting the replication of theHIV virus, treating AIDS or delaying the onset of AIDS in an individual(e.g., a human), comprising administering a compound of any formula (I),or a pharmaceutically acceptable salt thereof, to the individual isdisclosed.

In certain embodiments, a method for preventing an HIV infection in anindividual (e.g., a human), comprising administering a compound offormula (I), or a pharmaceutically acceptable salt thereof, to theindividual is disclosed. In certain embodiments, the individual is atrisk of contracting the HIV virus, such as an individual who has one ormore risk factors known to be associated with contracting the HIV virus.

In certain embodiments, a method for treating an HIV infection in anindividual (e.g., a human), comprising administering a compound offormula (I), or a pharmaceutically acceptable salt thereof, to theindividual is disclosed.

In certain embodiments, a method for treating an HIV infection in anindividual (e.g., a human), comprising administering to the individualin need thereof a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof, incombination with a therapeutically effective amount of one or moreadditional therapeutic agents selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, capsid polymerization inhibitors, and other drugs fortreating HIV, and combinations thereof is disclosed.

In certain embodiments, a compound of formula (I), or a pharmaceuticallyacceptable salt thereof for use in medical therapy of an HIV viralinfection (e.g. HIV-1 or the replication of the HIV virus (e.g. HIV-1)or AIDS or delaying the onset of AIDS in an individual (e.g., a human))is disclosed.

In certain embodiments, a compound of any of formula (I), or apharmaceutically acceptable salt thereof for use in the manufacture of amedicament for treating an HIV viral infection or the replication of theHIV virus or AIDS or delaying the onset of AIDS in an individual (e.g.,a human) is disclosed. One embodiment relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, for use in theprophylactic or therapeutic treatment of an HIV infection or AIDS or foruse in the therapeutic treatment or delaying the onset of AIDS isdisclosed.

In certain embodiments, the use of a compound of formula (I), or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for an HIV virus infection in an individual (e.g., a human)is disclosed. In certain embodiments, a compound of any of formula (I),or a pharmaceutically acceptable salt thereof, for use in theprophylactic or therapeutic treatment of an HIV virus infection isdisclosed.

In certain embodiments, in the methods of use, the administration is toan individual (e.g., a human) in need of the treatment. In certainembodiments, in the methods of use, the administration is to anindividual (e.g., a human) who is at risk of developing AIDS.

Disclosed herein is a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, for use in therapy. In one embodiment, thecompound of formula (I), or a pharmaceutically acceptable salt thereof,is for use in a method of treating an HIV viral infection or thereplication of the HIV virus or AIDS or delaying the onset of AIDS in anindividual (e.g., a human).

Also disclosed herein is a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in a method oftreating or preventing HIV in an individual in need thereof. In certainembodiments, the individual in need thereof is a human who has beeninfected with HIV. In certain embodiments, the individual in needthereof is a human who has been infected with HIV but who has notdeveloped AIDS. In certain embodiments, the individual in need thereofis an individual at risk for developing AIDS. In certain embodiments,the individual in need thereof is a human who has been infected with HIVand who has developed AIDS.

Also disclosed herein is a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in the therapeutictreatment or delaying the onset of AIDS.

Also disclosed herein is a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in the prophylactic ortherapeutic treatment of an HIV infection.

In certain embodiments, a compound of formula (I), or a pharmaceuticallyacceptable salt thereof can be used as a research tool (e.g. to studythe inhibition of HIV reverse transcriptase in a subject or in vitro).

Routes of Administration

One or more compounds disclosed herein which are of the Formula (I)(also referred to herein as the active ingredients) can be administeredby any route appropriate to the condition to be treated. Suitable routesinclude oral, rectal, nasal, topical (including buccal and sublingual),transdermal, vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. It will be appreciated that the preferred route may vary with,for example, the condition of the recipient. In certain embodiments, thecompounds disclosed are orally bioavailable and can be dosed orally.

Dosing Regimen

The compound, such as a compound of Formula (I), may be administered toan individual in accordance with an effective dosing regimen for adesired period of time or duration, such as at least about one month, atleast about 2 months, at least about 3 months, at least about 6 months,or at least about 12 months or longer. In one variation, the compound isadministered on a daily or intermittent schedule for the duration of theindividual's life.

The dosage or dosing frequency of a compound of Formula (I) may beadjusted over the course of the treatment, based on the judgment of theadministering physician.

The compound may be administered to an individual (e.g., a human) in aneffective amount. In certain embodiments, the compound is administeredonce daily.

A compound as disclosed herein (e.g., any compound of Formula (I)) maybe administered in a dosage amount of the compound of Formula I that iseffective. For example, the dosage amount can be from 10 mg to 1000 mgof compound, such as 75 mg to 100 mg of the compound.

Combinations

In certain embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isdisclosed, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents. In one embodiment, a method fortreating an HIV infection in a human having or at risk of having theinfection is disclosed, comprising administering to the human atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents.

In certain embodiments, the present disclosure relates to a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt, thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents which are suitable for treating an HIV infection.

Also disclosed herein is a compound of formula (I), or apharmaceutically acceptable salt thereof, and another active ingredientfor treating HIV, for use in a method of treating or preventing HIV. Inone embodiment, the another active ingredient for treating HIV isselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, and other drugs for treating HIV, and combinations thereof.

Also disclosed herein is a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in a method oftreating or preventing HIV, wherein the compound of formula (I) or apharmaceutically acceptable salt thereof is administered simultaneously,separately or sequentially with another active ingredient for treatingHIV. In one embodiment, the another active ingredient for treating HIVis selected from the group consisting of HIV protease inhibitingcompounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIVnucleoside inhibitors of reverse transcriptase, HIV nucleotideinhibitors of reverse transcriptase, HIV integrase inhibitors, gp41inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsidpolymerization inhibitors, and other drugs for treating HIV, andcombinations thereof.

A compound as disclosed herein (e.g., any compound of Formula (I)) maybe combined with one or more additional therapeutic agents in any dosageamount of the compound of Formula I (e.g., from 10 mg to 1000 mg ofcompound or 75 mg to 100 mg of compound).

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent or excipient are disclosed.

In one embodiment, kits comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents are disclosed.

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors (e.g., CCR5inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachmentinhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidaseinhibitors, HIV vaccines, HIV maturation inhibitors, latency reversingagents (e.g., histone deacetylase inhibitors, proteasome inhibitors,protein kinase C (PKC) activators, and BRD4 inhibitors), compounds thattarget the HIV capsid (“capsid inhibitors”; e.g., capsid polymerizationinhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7)inhibitors, HIV p24 capsid protein inhibitors), pharmacokineticenhancers, immune-based therapies (e.g., Pd-1 modulators, Pd-L1modulators, toll like receptors modulators, IL-15 agonists, ), HIVantibodies, bispecific antibodies and “antibody-like” therapeuticproteins (e.g., DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fabderivatives) including those targeting HIV gp120 or gp41, combinationdrugs for HIV, HIV p17 matrix protein inhibitors, IL-13 antagonists,Peptidyl-prolyl cis-trans isomerase A modulators, Protein disulfideisomerase inhibitors, Complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, HIV-1 viralinfectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nefmodulators, Hck tyrosine kinase modulators, mixed lineage kinase-3(MLK-3) inhibitors, Rev protein inhibitors, Integrin antagonists,Nucleoprotein inhibitors, Splicing factor modulators, COMM domaincontaining protein 1 modulators, HIV Ribonuclease H inhibitors,Retrocyclin modulators, CDK-9 inhibitors, Dendritic ICAM-3 grabbingnonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL proteininhibitors, Complement Factor H modulators, Ubiquitin ligase inhibitors,Deoxycytidine kinase inhibitors, Cyclin dependent kinase inhibitorsProprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3Xinhibitors, reverse transcriptase priming complex inhibitors, PI3Kinhibitors, compounds such as those disclosed in WO 2013/006738 (GileadSciences), US 2013/0165489 (University of Pennsylvania), WO2013/091096A1 (Boehringer Ingelheim), WO 2009/062285 (BoehringerIngelheim), US20140221380 (Japan Tobacco), US20140221378 (JapanTobacco), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (GileadSciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (GileadSciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (GileadSciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498 (GileadSciences) and WO 2013/006792 (Pharma Resources), and other drugs fortreating HIV, and combinations thereof.

In certain embodiments, the additional therapeutic is selected from thegroup consisting of HIV protease inhibitors, HIV non-nucleoside ornon-nucleotide inhibitors of reverse transcriptase, HIV nucleoside ornucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors,pharmacokinetic enhancers, and combinations thereof.

In certain embodiments a compound of Formula (I) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HIV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HIV, such as HIV protease inhibitors, HIVnon-nucleoside or non-nucleotide inhibitors of reverse transcriptase,HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, HIV non-catalytic site (or allosteric) integraseinhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.In certain embodiments, the additional therapeutic agent is selectedfrom one or more of:

(1) Combination drugs selected from the group consisting of ATRIPLA®(efavirenz+tenofovir disoproxil fumarate+emtricitabine), COMPLERA®(EVIPLERA®, rilpivirine+tenofovir disoproxil fumarate+emtricitabine),STRIBILD® (elvitegravir+cobicistat+tenofovir disoproxilfumarate+emtricitabine), dolutegravir+abacavir sulfate+lamivudine,dolutegravir+abacavir sulfate+lamivudine,lamivudine+nevirapine+zidovudine, dolutegravir+rilpivirine, atazanavirsulfate+cobicistat, darunavir+cobicistat, efavirenz+lamivudine+tenofovirdisoproxil fumarate, tenofovir alafenamidehemifumarate+emtricitabine+cobicistat+elvitegravir, Vacc-4x+romidepsin,darunavir+tenofovir alafenamide hemifumarate+emtricitabine+cobicistat,APH-0812, raltegravir+lamivudine, KALETRA® (ALUVIA®,lopinavir+ritonavir), atazanavir sulfate+ritonavir, COMBIVIR®(zidovudine+lamivudine, AZT+3TC), EPZICOM® (Livexa®, abacavirsulfate+lamivudine, ABC+3TC), TRIZIVIR® (abacavirsulfate+zidovudine+lamivudine, ABC+AZT+3TC), TRUVADA® (tenofovirdisoproxil fumarate+emtricitabine, TDF+FTC), tenofovir+lamivudine andlamivudine+tenofovir disoproxil fumarate;

(2) HIV protease inhibitors selected from the group consisting ofamprenavir, atazanavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, ritonavir, nelfinavir, nelfinavirmesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavir,darunavir, DG-17, TMB-657 (PPL-100) and TMC-310911;

(3) HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase selected from the group consisting of delavirdine,delavirdine mesylate, nevirapine, etravirine, dapivirine, doravirine,rilpivirine, efavirenz, KM-023, VM-1500, lentinan and AIC-292;

(4) HIV nucleoside or nucleotide inhibitors of reverse transcriptaseselected from the group consisting of VIDEX® and VIDEX® EC (didanosine,ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine,lamivudine, censavudine, abacavir, abacavir sulfate, amdoxovir,elvucitabine, alovudine, phosphazid, fozivudine tidoxil, apricitabine,amdoxovir, KP-1461, fosalvudine tidoxil, tenofovir, tenofovirdisoproxil, tenofovir disoproxil fumarate, tenofovir disoproxilhemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate,tenofovir alafenamide fumarate, adefovir, adefovir dipivoxil, andfestinavir;

(5) HIV integrase inhibitors selected from the group consisting ofcurcumin, derivatives of curcumin, chicoric acid, derivatives ofchicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, raltegravir, elvitegravir,dolutegravir and cabotegravir;

(6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI)selected from the group consisting of CX-05168, CX-05045 and CX-14442;

(7) HIV gp41 inhibitors selected from the group consisting ofenfuvirtide, sifuvirtide and albuvirtide;

(8) HIV entry inhibitors selected from the group consisting ofcenicriviroc;

(9) HIV gp120 inhibitors selected from the group consisting of Radha-108(Receptol) and BMS-663068;

(10) CCR5 inhibitors selected from the group consisting of aplaviroc,vicriviroc, maraviroc, cenicriviroc, PRO-140, Adaptavir (RAP-101),TBR-220 (TAK-220) and vMIP (Haimipu);

(11) CD4 attachment inhibitors selected from the group consisting ofibalizumab;

(12) CXCR4 inhibitors selected from the group consisting of plerixafor,ALT-1188, vMIP and Haimipu;

(13) Pharmacokinetic enhancers selected from the group consisting ofcobicistat and ritonavir;

(14) Immune-based therapies selected from the group consisting ofdermaVir, interleukin-7, lexgenleucel-T (VRX-496), plaquenil(hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa,interferon alfa-2b, interferon alfa-n3, pegylated interferon alfa,interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its esterderivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-2 XL,IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22,BMS-936559, toll-like receptors modulators (tlr1, tlr2, tlr3, tlr4,tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13),rintatolimod and IR-103;

(15) HIV vaccines selected from the group consisting of peptidevaccines, recombinant subunit protein vaccines, live vector vaccines,DNA vaccines, virus-like particle vaccines (pseudovirion vaccine),CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX),ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), Remune, ITV-1, ContreVir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409, Vacc-4x, Vacc-C5,VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G,VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, HIV-LAMP-vax,Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines,TatImmune, GTU-multiHIV (FIT-06), AGS-004, gp140[delta]V2.TV1+MF-59,rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV,TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123,Vichrepol, rAAV1-PG9DP, GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300,TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2,PreVaxTat, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201,MVA-CMDR and DNA-Ad5 gag/pol/nef/nev (HVTN505);

(16) HIV antibodies, bispecific antibodies and “antibody-like”therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®,TandAbs®, Fab derivatives) including BMS-936559, TMB-360 and thosetargeting HIV gp120 or gp41 selected from the group consisting ofbavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117,KD-247, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8 andVRC07;

(17) latency reversing agents selected from the group consisting ofHistone deacetylase inhibitors such as Romidepsin, vorinostat,panobinostat; Proteasome inhibitors such as Velcade; protein kinase C(PKC) activators such as Indolactam, Prostratin, Ingenol B andDAG-lactones, Ionomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15,JQ1, disulfram, and amphotericin B;

(18) HIV nucleocapsid p7 (NCp7) inhibitors selected from the groupconsisting of azodicarbonamide;

(19) HIV maturation inhibitors selected from the group consisting ofBMS-955176 and GSK-2838232;

(20) PI3K inhibitors selected from the group consisting of idelalisib,AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib,rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857,taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate,perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557,GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439,puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117,SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301 and CLR-1401;

(21) the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO2013/006738 (Gilead Sciences), US 2013/0165489 (University ofPennsylvania), US20140221380 (Japan Tobacco), US20140221378 (JapanTobacco), WO 2013/006792 (Pharma Resources), WO 2009/062285 (BoehringerIngelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/091096A1(Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728(Gilead Sciences), WO2012/003497 (Gilead Sciences), WO2014/100323(Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064(Gilead Sciences) and WO 2012/003498 (Gilead Sciences); and

(22) other drugs for treating HIV selected from the group consisting ofTR-452, MK-8591, REP 9, CYT-107, alisporivir, NOV-205, IND-02,metenkefalin, PGN-007, Acemannan, Gamimune, SCY-635, Prolastin,1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO-3100,SB-728-T, RPI-MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazFgene therapy, BlockAide and PA-1050040 (PA-040).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents. In aspecific embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase and an HIV non-nucleosideinhibitor of reverse transcriptase. In another specific embodiment, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with an HIV nucleoside or nucleotide inhibitor ofreverse transcriptase, and an HIV protease inhibiting compound. In afurther embodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, an HIV non-nucleosideinhibitor of reverse transcriptase, and an HIV protease inhibitingcompound. In an additional embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase, an HIVnon-nucleoside inhibitor of reverse transcriptase, and a pharmacokineticenhancer. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with at least oneHIV nucleoside inhibitor of reverse transcriptase, an integraseinhibitor, and a pharmacokinetic enhancer. In another embodiment, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with two HIV nucleoside or nucleotide inhibitors ofreverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected fromraltegravir, Truvada® (tenofovir disoproxil fumarate+emtricitabine,TDF+FTC), maraviroc, enfuvirtide, Epzicom® (Livexa®, abacavirsulfate+lamivudine, ABC+3TC), Trizivir® (abacavirsulfate+zidovudine+lamivudine, ABC+AZT+3TC), adefovir, adefovirdipivoxil, Stribild® (elvitegravir+cobicistat+tenofovir disoproxilfumarate+emtricitabine), rilpivirine, rilpivirine hydrochloride,Complera® (Eviplera®, rilpivirine+tenofovir disoproxilfumarate+emtricitabine), Cobicistat, Atripla® (efavirenz+tenofovirdisoproxil fumarate+emtricitabine), atazanavir, atazanavir sulfate,dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir),ritonavir, emtricitabine, atazanavir_sulfate+ritonavir, darunavir,lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz,Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir,nelfinavir mesylate, interferon, didanosine, stavudine, indinavir,indinavir sulfate, tenofovir+lamivudine, zidovudine, nevirapine,saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir,amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol),Hlviral, lamivudine+tenofovir disoproxil fumarate,efavirenz+lamivudine+tenofovir disoproxil fumarate, phosphazid,lamivudine+nevirapine+zidovudine, abacavir, abacavir sulfate, tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide and tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide or tenofoviralafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarateand a second additional therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting of:tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, and tenofovir alafenamide hemifumarate and asecond additional therapeutic agent, wherein the second additionaltherapeutic agent is emtricitabine.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30;or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 10 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamideand 200 mg emtricitabine. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. Acompound as disclosed herein (e.g., a compound of formula (I)) may becombined with the agents disclosed herein in any dosage amount of thecompound (e.g., from 10 mg to 1000 mg of compound, 10 mg to 500 mg, or75 mg to 100 mg of compound) the same as if each combination of dosageswere specifically and individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil and 200 mg emtricitabine. In certain embodiments, acompound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 200-250; 200-300; 200-350; 250-350; 250-400;350-400; 300-400; or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil and 200 mgemtricitabine. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of formula (I)) may be combined with the agentsdisclosed herein in any dosage amount of the compound (e.g., from 10 mgto 1000 mg of compound, 10 mg to 500 mg, or 75 mg to 100 mg of compound)the same as if each combination of dosages were specifically andindividually listed.

In certain embodiments, when a compound disclosed herein is combinedwith one or more additional therapeutic agents as described above, thecomponents of the composition are administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments, a compound disclosed herein is administered withone or more additional therapeutic agents. Co-administration of acompound disclosed herein with one or more additional therapeutic agentsgenerally refers to simultaneous or sequential administration of acompound disclosed herein and one or more additional therapeutic agents,such that therapeutically effective amounts of the compound disclosedherein and one or more additional therapeutic agents are both present inthe body of the patient.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents, for example,administration of the compound disclosed herein within seconds, minutes,or hours of the administration of one or more additional therapeuticagents. For example, in some embodiments, a unit dose of a compounddisclosed herein is administered first, followed within seconds orminutes by administration of a unit dose of one or more additionaltherapeutic agents. Alternatively, in other embodiments, a unit dose ofone or more additional therapeutic agents is administered first,followed by administration of a unit dose of a compound disclosed hereinwithin seconds or minutes. In some embodiments, a unit dose of acompound disclosed herein is administered first, followed, after aperiod of hours (e.g., 1-12 hours), by administration of a unit dose ofone or more additional therapeutic agents. In other embodiments, a unitdose of one or more additional therapeutic agents is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound disclosed herein.

In certain embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, in combination with a therapeutically effectiveamount of one or more (e.g., one, two, three, one or two, or one tothree) additional therapeutic agents. In one embodiment, a method fortreating an HIV infection in a human having or at risk of having theinfection is provided, comprising administering to the human atherapeutically effective amount of a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,one or two, or one to three) additional therapeutic agents.

In one embodiment, pharmaceutical compositions comprising a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, incombination with one or more (e.g., one, two, three, one or two, or oneto three) additional therapeutic agents, and a pharmaceuticallyacceptable carrier, diluent, or excipient are provided.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a patient in needthereof a therapeutically effective amount of a compound disclosedherein, or a pharmaceutically acceptable salt thereof, in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents which are suitable for treating an HIV infection.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four, or more additional therapeutic agents. In certainembodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two additional therapeuticagents. In other embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compounddisclosed herein, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four, or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

Administration of HIV Combination Therapy

In certain embodiments, a compound disclosed herein is administered withone or more additional therapeutic agents. Co-administration of acompound disclosed herein with one or more additional therapeutic agentsgenerally refers to simultaneous or sequential administration of acompound disclosed herein and one or more additional therapeutic agents,such that therapeutically effective amounts of the compound disclosedherein and the one or more additional therapeutic agents are bothpresent in the body of the patient. When administered sequentially, thecombination may be administered in two or more administrations.

Co-administration includes administration of unit dosages of thecompounds disclosed herein before or after administration of unitdosages of one or more additional therapeutic agents. For example, thecompound disclosed herein may be administered within seconds, minutes,or hours of the administration of the one or more additional therapeuticagents. In some embodiments, a unit dose of a compound disclosed hereinis administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents. Alternatively, a unit dose of one or more additional therapeuticagents is administered first, followed by administration of a unit doseof a compound disclosed herein within seconds or minutes. In otherembodiments, a unit dose of a compound disclosed herein is administeredfirst, followed, after a period of hours (e.g., 1-12 hours), byadministration of a unit dose of one or more additional therapeuticagents. In yet other embodiments, a unit dose of one or more additionaltherapeutic agents is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of a compounddisclosed herein.

In certain embodiments, a compound disclosed herein is combined with oneor more additional therapeutic agents in a unitary dosage form forsimultaneous administration to a patient, for example as a solid dosageform for oral administration.

In certain embodiments, a compound of Formula (I) is formulated as atablet, which may optionally contain one or more other compounds usefulfor treating HIV. In certain embodiments, the tablet can contain anotheractive ingredient for treating HIV, such as HIV protease inhibitors, HIVnon-nucleoside or non-nucleotide inhibitors of reverse transcriptase,HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, HIV non-catalytic site (or allosteric) integraseinhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

HIV Combination Therapy

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent. For example, in some embodiments, the additionaltherapeutic agent is selected from the group consisting of combinationdrugs for HIV, other drugs for treating HIV, HIV protease inhibitors,HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors, HIV maturationinhibitors, latency reversing agents, compounds that target the HIVcapsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K)inhibitors, HIV antibodies, bispecific antibodies and “antibody-like”therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13antagonists, peptidyl-prolyl cis-trans isomerase A modulators, proteindisulfide isomerase inhibitors, complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, Vif dimerizationantagonists, HIV-1 viral infectivity factor inhibitors, TAT proteininhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixedlineage kinase-3 (MILK-3) inhibitors, HIV-1 splicing inhibitors, Revprotein inhibitors, integrin antagonists, nucleoprotein inhibitors,splicing factor modulators, COMM domain containing protein 1 modulators,HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovirdisoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®;rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, andemtricitabine); TRUVADA® (tenofovir disoproxil fumarate andemtricitabine; TDF+FTC); darunavir, tenofovir alafenamide hemifumarate,emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; lamivudine and tenofovir disoproxil fumarate;tenofovir and lamivudine; tenofovir alafenamide and emtricitabine;tenofovir alafenamide, emtricitabine, and rilpivirine; tenofoviralafenamide hemifumarate and emtricitabine; tenofovir alafenamidehemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamidehemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR®(zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavirsulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir andritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR®(abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavirand cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfateand ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine;dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavirsulfate, and lamivudine; lamivudine, nevirapine, and zidovudine;raltegravir and lamivudine; doravirine, lamivudine, and tenofovirdisoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil;lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4× and romidepsin;and APH-0812.

Other HIV Drugs

Examples of other drugs for treating HIV include acemannan, alisporivir,BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP9, RPI-MN, VSSP, Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid,rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy,BlockAide, ABX-464, AG-1105, BIT-225, CYT-107, HGTV-43, HS-10234,IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040(PA-040), PGC-007, SCY-635, TR-452, TEV-90110, TEV-90112, TEV-90111,TEV-90113, RN-18, Immuglo, and VIR-576.

HIV Protease Inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir,brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate,ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase include dapivirine, delavirdine, delavirdine mesylate,doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine,AIC-292, KM-023, and VM-1500.

Examples of HIV nucleoside or nucleotide inhibitors of reversetranscriptase include adefovir, adefovir dipivoxil, emtricitabine,tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate,tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovirdisoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEXEC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, fozivudine tidoxil, lamivudine, phosphazid,stavudine, zalcitabine, zidovudine, and KP-1461.

HIV Integrase Inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin,derivatives of curcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, raltegravir, dolutegravir, JTK-351, and cabotegravir.

Examples of HIV non-catalytic site, or allosteric, integrase inhibitors(NCINI) include CX-05045, CX-05168, T-169, and CX-14442.

HIV Entry Inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc,cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232),TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide, andsifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab.

Examples of gp120 inhibitors include Radha-108 (receptol) and BMS-663068

Examples of CXCR4 inhibitors include plerixafor, and vMIP (Haimipu).

HIV Maturation Inhibitors

Examples of HIV maturation inhibitors include BMS-955176 andGSK-2838232.

Latency Reversing Agents

Examples of latency reversing agents include histone deacetylase (HDAC)inhibitors, proteasome inhibitors such as velcade, protein kinase C(PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA,SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamicacid), IL-15, JQ1, disulfram, amphotericin B, and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, andpanobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B,and DAG-lactones.

Capsid Inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitorsor capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitorssuch as azodicarbonamide, and HIV p24 capsid protein inhibitors.

Immune-Based Therapies

Examples of immune-based therapies include toll-like receptorsmodulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9,tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1)modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15agonists; DermaVir; interleukin-7; plaquenil (hydroxychloroquine);proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b;interferon alfa-n3; pegylated interferon alfa; interferon gamma;hydroxyurea; mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI);gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; GS-9620; BMS-936559;and IR-103.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib,CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib,perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib,rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439,CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577,GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666,RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857,VS-5584, XL-765, and ZSTK-474.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” TherapeuticProteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like”therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, BMS-936559, TMB-360, and those targeting HIVgp120 or gp41.

Examples of those targeting HIV gp120 or gp41 include bavituximab,UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121,MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523, MGD-014 andVRC07.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents

Examples of additional therapeutic agents include the compoundsdisclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (GileadSciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (GileadSciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (GileadSciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (GileadSciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (Universityof Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences); WO 2013/091096 (Boehringer Ingelheim);and U.S. 20100143301 (Gilead Sciences).

HIV Vaccines

Examples of HIV vaccines include peptide vaccines, recombinant subunitprotein vaccines, live vector vaccines, DNA vaccines, CD4-derivedpeptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV(vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype Cvaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401),Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5(rAd5), Pennvax-G, Pennvax-GP, VRC-HIV MAB060-00-AB, HIV-TriMix-mRNAvaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLCadjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06),gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine,AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1,NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21,TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2,PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR,DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401,rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201,PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, andvirus-like particle vaccines such as pseudovirion vaccine.

HIV Combination Therapy

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents selected from ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA®(EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); adefovir; adefovir dipivoxil;cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovirdisoproxil fumarate; tenofovir alafenamide; tenofovir alafenamidehemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine);dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravirand lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); Hlviral;lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, andtenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, andzidovudine; abacavir; and abacavir sulfate.

In a specific embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase and an HIVnon-nucleoside inhibitor of reverse transcriptase. In another specificembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase, and an HIV proteaseinhibiting compound. In an additional embodiment, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withan HIV nucleoside or nucleotide inhibitor of reverse transcriptase, anHIV non-nucleoside inhibitor of reverse transcriptase, and apharmacokinetic enhancer. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined withat least one HIV nucleoside inhibitor of reverse transcriptase, anintegrase inhibitor, and a pharmacokinetic enhancer. In anotherembodiment, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with two HIV nucleoside ornucleotide inhibitors of reverse transcriptase.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofoviralafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with tenofovir,tenofovir disoproxil, tenofovir disoproxil fumarate, tenofoviralafenamide, or tenofovir alafenamide hemifumarate.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting ofabacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate,and a second additional therapeutic agent selected from the groupconsisting of emtricitabine and lamivudine.

In a particular embodiment, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with a firstadditional therapeutic agent selected from the group consisting oftenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and asecond additional therapeutic agent, wherein the second additionaltherapeutic agent is emtricitabine.

A compound as disclosed herein (e.g., any compound of Formula (I)) maybe combined with one or more additional therapeutic agents in any dosageamount of the compound of Formula (I) (e.g., from 50 mg to 1000 mg ofcompound).

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 5-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, ortenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30,or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Incertain embodiments, a compound disclosed herein, or a pharmaceuticallyacceptable salt thereof, is combined with 10 mg tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide,and 200 mg emtricitabine. In certain embodiments, a compound disclosedherein, or a pharmaceutically acceptable salt thereof, is combined with25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Acompound as disclosed herein (e.g., a compound of formula (I)) may becombined with the agents provided herein in any dosage amount of thecompound (e.g., from 50 mg to 500 mg of compound) the same as if eachcombination of dosages were specifically and individually listed.

In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 200-400 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments,a compound disclosed herein, or a pharmaceutically acceptable saltthereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400,350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. In certain embodiments, a compound disclosed herein, or apharmaceutically acceptable salt thereof, is combined with 300 mgtenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, ortenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosedherein (e.g., a compound of formula (I)) may be combined with the agentsprovided herein in any dosage amount of the compound (e.g., from 50 mgto 500 mg of compound) the same as if each combination of dosages werespecifically and individually listed.

In one embodiment, kits comprising a compound disclosed herein, or apharmaceutically acceptable salt thereof, in combination with one ormore (e.g., one, two, three, one or two, or one to three) additionaltherapeutic agents are provided.

Kits and Articles of Manufacture

The present disclosure relates to a kit comprising a compound of formula(I), or a pharmaceutically acceptable salt thereof. The kit may furthercomprise instructions for use, e.g., for use in inhibiting an HIVreverse transcriptase, such as for use in treating an HIV infection orAIDS or as a research tool. The instructions for use are generallywritten instructions, although electronic storage media (e.g., magneticdiskette or optical disk) containing instructions are also acceptable.

The present disclosure also relates to a pharmaceutical kit comprisingone or more containers comprising a compound of any of formula (I), or apharmaceutically acceptable salt thereof. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals, which notice reflects approval by the agency for themanufacture, use or sale for human administration. Each component (ifthere is more than one component) can be packaged in separate containersor some components can be combined in one container wherecross-reactivity and shelf life permit. The kits may be in unit dosageforms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kitsmay also include multiple unit doses of the compounds and instructionsfor use and be packaged in quantities sufficient for storage and use inpharmacies (e.g., hospital pharmacies and compounding pharmacies).

Also disclosed are articles of manufacture comprising a unit dosage of acompound of any of formula (I), or a pharmaceutically acceptable saltthereof, in suitable packaging for use in the methods described herein.Suitable packaging is known in the art and includes, for example, vials,vessels, ampules, bottles, jars, flexible packaging and the like. Anarticle of manufacture may further be sterilized and/or sealed.

The present disclosure is also directed to processes and intermediatesuseful for preparing the subject compounds or pharmaceuticallyacceptable salts thereof.

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith, March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 7^(th) edition,Wiley-Interscience, 2013.)

Compounds as described herein can be purified by any of the means knownin the art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography. See, e.g.,Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyderand J. J. Kirkland, John Wiley and Sons, 1979; and Thin LayerChromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 4^(th) ed., Wiley, New York 2006. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemes ispreferably run at a temperature from about 0° C. to the refluxtemperature of the organic solvent used. Unless otherwise specified, thevariables are as defined above in reference to formula (I).

Representative syntheses of compounds of the present disclosure aredescribed in schemes below, and the particular examples that follow.

The embodiments are also directed to processes and intermediates usefulfor preparing the subject compounds or pharmaceutically acceptable saltsthereof.

Many general references providing commonly known chemical syntheticschemes and conditions useful for synthesizing the disclosed compoundsare available (see, e.g., Smith, March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 7^(th) edition,Wiley-Interscience, 2013.). Angew. Chem. Int. Ed. 2014, 53, 2-21, whichis herein incorporated by reference in its entirety, provides a reviewof sulfur (VI) fluoride exchange, which can also be useful in thesynthetic schemes.

Compounds as described herein can be purified by any of the means knownin the art, including chromatographic means, such as high performanceliquid chromatography (HPLC), preparative thin layer chromatography,flash column chromatography and ion exchange chromatography. Anysuitable stationary phase can be used, including normal and reversedphases as well as ionic resins. Most typically the disclosed compoundsare purified via silica gel and/or alumina chromatography. See, e.g.,Introduction to Modem Liquid Chromatography, 2nd ed., ed. L. R. Snyderand J. J. Kirkland, John Wiley and Sons, 1979; and Thin LayerChromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any of the processes for preparation of the subject compounds, itmay be necessary and/or desirable to protect sensitive or reactivegroups on any of the molecules concerned. This may be achieved by meansof conventional protecting groups as described in standard works, suchas T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis,” 4^(th) ed., Wiley, New York 2006. The protecting groups maybe removed at a convenient subsequent stage using methods known from theart.

Exemplary chemical entities useful in methods of the embodiments willnow be described by reference to illustrative synthetic schemes fortheir general preparation herein and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Furthermore, one of skill in the art will recognizethat the transformations shown in the schemes below may be performed inany order that is compatible with the functionality of the particularpendant groups. Each of the reactions depicted in the general schemesmay be run at a temperature from about 0° C. to the reflux temperatureof the organic solvent used. Unless otherwise specified, the variablesare as defined above in reference to formula (I).

Representative syntheses of compounds of the present disclosure aredescribed in schemes below, and the particular examples that follow.

Scheme 1 shows a representative synthesis of the compounds of theembodiments. The methodology is compatible with a wide variety offunctionalities.

In Scheme 1, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X¹, X², X³, and Q are asdefined herein. Also in Scheme 1, as discussed below, Y^(1a), Z^(1a),and Z^(2a) are precursor moieties to forming the proper bonds andmoieties in formula (I). Starting materials may be obtained fromcommercial sources or via well-established synthetic procedures. Thesynthesis of formula 1-D is discussed below in Schemes 4 and 5.

In Scheme 1, a nucleophilic substitution reaction between formula 1-Aand 1-B occurs to produce a compound of formula 1-C. The amino group offormula 1-B reacts with formula 1-A to displace Y^(1a), which is aleaving group, such as halogen, triflate, mesylate, and tosylate. Incertain instances, Y^(1a) is halogen, such as iodo, bromo, or chloro.

With continued reference to Scheme 1, a coupling reaction betweenformula 1-C and 1-D occurs to produce a compound of formula (I). Incertain instances, a palladium-catalyzed reaction between an aryl halideand an organoboron compound (e.g., Suzuki coupling reaction) can beused. With a Suzuki coupling reaction, Z^(1a) in formula 1-C can be ahalide, such as iodo or bromo and Z^(2a) in formula 1-D can be a boronicacid or boronic acid ester. In certain instances, Z²a is

In certain instances, the coupling step includes a palladium catalyst,such as 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichlorideor 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride.

With continued reference to Scheme 1, as an alternative couplingreaction between formula 1-C and 1-D, a palladium-catalyzed reactionbetween an organotin compound and an aryl halide (e.g., Stille couplingreaction) can be used to produce a compound of formula (I). With theStille reaction, Z^(1a) in formula 1-C can be an organotin moiety(—SnR₄, where R is an alkyl group) and Z^(2a) in formula 1-D can be ahalide, such as iodo, or bromo. In certain instances, the coupling stepincludes a palladium catalyst, such asbis(tri-tert-butylphosphine)palladium(0).

Scheme 2 is another representative synthesis of the compounds of theembodiments. The methodology is compatible with a wide variety offunctionalities.

In Scheme 2, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X¹, X², X³, and Qare as defined herein. Also in Scheme 2, as discussed below, Y^(1a),Z^(1a), and Z^(2a) are precursor moieties to forming the proper bondsand moieties in formula (I). Starting materials may be obtained fromcommercial sources or via well-established synthetic procedures.

In Scheme 2, a nucleophilic substitution reaction between formula 2-Aand 2-B occurs to produce a compound of formula 2-C. The amino group offormula 2-B reacts with formula 2-A to displace Y^(1a), which is aleaving group, such as halogen, triflate, mesylate, and tosylate. Incertain instances, Y^(1a) is halogen, such as iodo, bromo, or chloro.

With continued reference to Scheme 2, a coupling reaction betweenformula 2-C and 2-D occurs to produce formula 2-E. In certain instances,a palladium-catalyzed reaction between an aryl halide and an organoboroncompound (e.g., Suzuki coupling reaction) can be used. With a Suzukicoupling reaction, Zia in formula 2-C can be a halide, such as iodo orbromo and Z^(2a) in formula 2-D can be a boronic acid or boronic acidester. In certain instances, Z^(2a) is

In certain instances, the coupling step includes a palladium catalyst,such as 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichlorideor 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride.

With continued reference to Scheme 2, as an alternative couplingreaction between formula 2-C and 2-D, a palladium-catalyzed reactionbetween an organotin compound and an aryl halide (e.g., Stille couplingreaction) can be used to produce a compound of formula (I). With theStille reaction, Zia in formula 2-C can be an organotin moiety (—SnR₄,where R is an alkyl group) and Z^(2a) in formula 2-D can be a halide,such as iodo or bromo. In certain instances, the coupling step includesa palladium catalyst, such as bis(tri-tert-butylphosphine)palladium(0).

With continued reference to Scheme 2, a coupling reaction betweenformula 2-D and 2-E occurs to produce a compound of formula (I). Incertain instances, a coupling reaction between a stabilized phosphonatecarbanion and an aldehyde (e.g., Horner-Wadsworth-Emmons reaction) canbe used.

Scheme 3 is another representative synthesis of the compounds of theembodiments. The methodology is compatible with a wide variety offunctionalities.

In Scheme 3, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X¹, X², X³, and Q are asdefined herein. Also in Scheme 3, as discussed below, Y^(1a), Z^(1a),and Z^(2a) are precursor moieties to forming the proper bonds andmoieties in formula (I). Starting materials may be obtained fromcommercial sources or via well-established synthetic procedures. Thesynthesis of formula 1-D is discussed below in Schemes 4 and 5.

With reference to Scheme 3, a coupling reaction between formula 3-A and1-D occurs to produce formula 3-B. In certain instances, apalladium-catalyzed reaction between an aryl halide and an organoboroncompound (e.g., Suzuki coupling reaction) can be used. With a Suzukicoupling reaction, Z^(1a) in formula 3-A can be a halide, such as iodoor bromo and Z^(2a) in formula 1-D can be a boronic acid or boronic acidester. In certain instances, Z^(2a) is

In certain instances, the coupling step includes a palladium catalyst,such as 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichlorideor 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride.

With continued reference to Scheme 3, as an alternative couplingreaction between formula 3-A and 1-D, a palladium-catalyzed reactionbetween an organotin compound and an aryl halide (e.g., Stille couplingreaction) can be used to produce a compound of formula (I). With theStille reaction, Z^(1a) in formula 1-C can be an organotin moiety(—SnR₄, where R is an alkyl group) and Z^(2a) in formula 1-D can be ahalide, such as iodo, or bromo. In certain instances, the coupling stepincludes a palladium catalyst, such asbis(tri-tert-butylphosphine)palladium(0).

With continued reference to Scheme 3, a nucleophilic substitutionreaction between formula 3-B and 3-C occurs to produce a compound offormula (I). The amino group of formula 3-C reacts with formula 3-B todisplace Y^(1a), which is a leaving group, such as halogen, triflate,mesylate, and tosylate. In certain instances, Y^(1a) is halogen, such asiodo, bromo, or chloro.

Scheme 4 shows a representative synthesis of formula 1-D. Themethodology is compatible with a wide variety of functionalities.

In Scheme 4, R⁷, R⁸, R⁹, R¹⁰, and Q are as defined herein. Also inScheme 4, as discussed below, Q^(1a), X^(1a), and X^(2a) are precursormoieties to forming the proper bonds and moieties in formula 1-D.Starting materials may be obtained from commercial sources or viawell-established synthetic procedures.

In Scheme 4, a coupling reaction between formula 4-A and 4-B occurs toproduce formula 4-C. In certain instances, a palladium-catalyzedreaction between an aryl halide and an alkene compound (e.g., Heckcoupling reaction) can be used. With a Heck coupling reaction, X^(1a) informula 4-A can be a halide, such as iodo, or bromo and X^(2a) informula 4-B can be hydrogen. The Heck coupling reaction can be carriedout in the presence of a palladium catalyst, such as palladium(II)acetate in a combination with tri(o-tolyl)phosphine.

With continued reference to Scheme 4, Q^(1a) in formula 4-A and 4-C is aprecursor moiety to a boronic acid or boronic acid ester in formula 1-D,wherein Z^(2a) is a boronic acid or boronic acid ester. A borylationreaction of formula 4-C occurs to produce a compound of formula 1-D. Incertain instances, a cross-coupling reaction of4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) with an arylhalide (e.g., Miyaura borylation reaction) can be used. With a Miyauraborylation reaction, Q^(1a) in formula 4-C can be a halide, such asiodo, or bromo. In certain instances, Formula 4-C can react with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to providefor formula 1-D, in which Z^(2a) is

In certain instances, the borylation step includes a palladium catalyst,such as palladium(II) acetate in a combination withdicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine. Otherborylation reactions can be used.

Scheme 5 shows another representative synthesis of formula 1-D. Themethodology is compatible with a wide variety of functionalities.

In Scheme 5, R⁷, R⁸, R⁹, R¹⁰, and Q are as defined herein. Also inScheme 5, as discussed below, Q^(1a) and X^(1a) are precursor moietiesto forming the proper bonds and moieties in formula 1-D. Startingmaterials may be obtained from commercial sources or viawell-established synthetic procedures.

In Scheme 5, a coupling reaction between formula 5-A and 5-B occurs toproduce formula 5-C. In certain instances, a coupling reaction between astabilized phosphonate carbanion and an aldehyde (e.g.,Horner-Wadsworth-Emmons reaction) can be used. With aHorner-Wadsworth-Emmons reaction, X^(1a) in formula 4-A can be analdehyde or ketone (e.g., X^(1a) is —CHO or —C(O)R⁹).

With continued reference to Scheme 5, Q^(1a) in formula 5-A and 5-C is aprecursor moiety to a boronic acid in formula 1-D, wherein Z^(2a) is aboronic acid. A borylation reaction of formula 5-C occurs to produce acompound of formula 1-D. In certain instances, a cross-coupling reactionof 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) with anaryl halide (e.g., Miyaura Borylation reaction) can be used. With aMiyaura Borylation reaction, Q^(1a) in formula 5-C can be a halide, suchas iodo, or bromo In certain instances, Formula 5-C can react with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to providefor formula 1-D, in which Z^(2a) is

In certain instances, the borylation step includes a palladium catalyst,such as palladium(II) acetate in a combination withdicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine. Otherborylation reactions can be used.

Accordingly, and as described in more detail herein, the presentdisclosure relates to a process of preparing a compound of the presentdisclosure, the process involving:

reacting a compound of formula:

with a compound of formula:

thereby producing a compound of formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, X¹, X², X³, Z^(1a), Z^(2a), andQ are as defined herein.

Accordingly, and as described in more detail herein, the presentdisclosure relates to a process of preparing a compound of the presentdisclosure, the process involving:

reacting a compound of formula:

with a compound of formula:

thereby producing a compound of formula

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X¹, X², X³, Y^(1a), and Q are asdefined herein.

In certain instances, the above processes further involve the step offorming a salt of a compound of the present disclosure. Embodiments aredirected to the other processes described herein; and to the productprepared by any of the processes described herein.

Except as otherwise noted, the methods and techniques of the presentembodiments are generally performed according to conventional methodswell known in the art and as described in various general and morespecific references that are cited and discussed throughout the presentspecification. See, e.g., Loudon, Organic Chemistry, 5^(th) edition, NewYork: Oxford University Press, 2009; Smith, March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 7^(th) edition,Wiley-Interscience, 2013.

LIST OF ABBREVIATIONS AND ACRONYMS

Abbreviation—Meaning

Ac—Acetyl

B₂pin₂—4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane)

bs—Broad singlet

° C.—Degree Celsius

d—Doublet

DCM—Dichloromethane

dd—Doublet of doublet

DIPEA—N,N-Diisopropylethylamine

DMF—N,N-Dimethylformamide

DMSO—Dimethylsulfoxide

dppf—1,1′-Bis(diphenylphosphino)ferrocene

dtbpf—1,1′-Bis(di-tert-butylphosphino)ferrocene

EC₅₀—Half maximal effective concentration

Equiv/eq—Equivalents

Et—Ethyl

EtOH—Ethanol

g—Grams

HPLC—High-performance liquid chromatography

hrs/h—Hours

Hz—Hertz

J—Coupling constant

LCMS—Liquid chromatography-mass spectrometry

M—Molar

m—Multiplet

m/z—mass-to-charge ratio

M+—Mass peak

Me—Methyl

mg—Milligram

MHz—Megahertz

min—Minute

mL—Milliliter

mM—Millimolar

mm—Millimeter

mmol—Millimole

mol—Mole

MS—mass spectrometry

MW—Microwave

nM—Nanomolar

NMP—N-Methyl-2-pyrrolidone

NMR—Nuclear magnetic resonance

P(oTol)₃—Tri(o-tolyl)phosphine

P(t-Bu)₃—Tri-tert-butylphosphine

Pd₂(dba)₃—Tris(dibenzylideneacetone)palladium(0)

q—Quartet

quant—Quantitative

Rf—Retention factor

RT/rt/r.t.—Room temperature

s—Singlet

sat.—Saturated

SPhos—Dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine

t—Triplet

TFA—Trifluoroacetic acid

TMS—Trimethylsilyl

Tr/tr—Retention time

UV—Ultraviolet

wt.—Weight

Xantphos—(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

δ—Chemical shift

L—Microliter

M—Micromolar

mol—Micromole

The following examples are merely illustrative, and do not limit thisdisclosure in any way. Unless otherwise stated, preparative HPLC wasperformed on a Gilson HPLC system, using a 21.2×250 mm 10 micron C18Phenomenex Gemini semi-preparative column and gradient 0-100%acetonitrile in water mobile phase with 0.1% trifluoroacetic acid at aflow rate of 20 mL/min.

Chemical names for all prepared compounds were generated usingChemBioDraw 12.0 software.

While the structures in the examples below are drawn as certaingeometric isomers, a certain geometric isomer (e.g., E or Z isomer) or aratio of the E and Z isomers may be indicated in the title and/ordescription of the example to represent the results of the example.

The following methods were used for the purification andcharacterization of certain compounds described in the followingExamples.

LCMS method 1—Phenomenex Gemini-NX 3u C18 110 Å, 100×2 mm 3 microncolumn, Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid;0 min-7.0 min 0-100% ACN, flow rate 0.5 mL/min.

LCMS method 2—Gemini 5u C18 110 Å, 50×4.60 mm 5 micron column;Acetonitrile with 0.1% acetic acid, Water with 0.1% acetic acid;Gradient: 0 min-3.5 min 5-100% ACN; flow rate 2 mL/min.

LCMS method 3—Kinetex 2.6μ C18 100 Å, 50×3.00 mm column; Acetonitrilewith 0.1% formic acid, Water with 0.1% formic acid; Gradient: 0 min-1.4min 2-100% ACN, 1.4 min-1.8 min 100% ACN, 1.8 min-1.85 min 100%-2% ACN,1.85 min-2 min 2% ACN; flow rate 1.8 mL/min.

EXAMPLE 1(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile-Compound1

Step 1: Synthesis of 4-((8-bromoquinazolin-2-yl)amino)benzonitrile(Compound 1a)

A mixture of 8-bromo-2-chloroquinazoline (1.0 g, 4.10 mmol, Ark PharmInc, AK-27609) and 4-cyanoaniline (533 mg, 4.52 mmol, Sigma-Aldrich) inisopropanol (15 mL) was heated under reflux for 15 hours. The solidproduct was filtered off and washed twice with cold isopropanol (2×10mL). The product was dried on air to afford the title compound 1a. ¹HNMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 9.47 (s, 1H), 8.41 (d, J=8.8 Hz,2H), 8.28 (dd, J=7.8, 1.2 Hz, 1H), 8.06 (dd, J=7.8, 1.2 Hz, 1H), 7.85(d, J=8.8 Hz, 2H), 7.44 (t, J=7.8 Hz, 1H). HRMS: (ESI+) calculated forC₁₅H₁₀N₄Br [M+H] 325.00834, found 325.00821. LCMS (m/z) 325.0 [M+H],Tr=4.69 min (LCMS method 1).

Step 2: Synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile(Compound 1b)

To a solution of 2,5-dibromo-1,3-dimethylbenzene (2640 mg, 10 mmol,Oakwood Products, Inc.—018507) in anhydrous acetonitrile (25 mL) wasadded palladium(II) acetate (112 mg, 0.5 mmol), acrylonitrile (531 mg,10 mmol), tri(o-tolyl)phosphine (131 mg, 0.5 mmol) and triethylamine (4mL, 30 mmol) then the mixture was purged with argon and heated at 110°C. for 2 hours. The reaction mixture was filtered through Celite and thefilter pad was washed with tetrahydrofuran (10 mL). The filtrate wasevaporated then re-dissolved with ethyl acetate (50 mL). The solutionwas washed with water (50 mL). The water layer was back extracted withethyl acetate (50 mL). The combined organics were washed with brine (30mL), dried over sodium sulfate, filtered and concentrated under reducedpressure to give a crude residue. This was subjected to silica gelchromatography (gradient from 0-20% ethyl acetate in iso-hexanes) toafford the crude product which was treated in sonic bath with hexane (10mL) for 10 minutes. The product precipitated out of solution and wascollected by filtration. The solids were washed with cold hexane toafford compound 1b. ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, J=16.6 Hz, 1H),7.12 (s, 2H), 5.84 (d, J=16.6 Hz, 1H), 2.42 (s, 6H). LCMS (m/z) no MSsignal, Tr=2.78 min (LCMS method 2).

Step 3: Synthesis of(E)-3-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylonitrile(Compound 1c)

A mixture of compound 1b (391 mg, 1.66 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (630 mg,2.48 mmol), potassium carbonate (687 mg, 5 mmol), palladium(II) acetate(19 mg, 0.08 mmol) anddicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (SPhos, 85mg, 0.21 mmol) in dry N,N-dimethylformamide (20 mL) was purged withargon and heated at 100° C. for 1 hour. The reaction mixture wasfiltered through Celite and the filter pad was washed withtetrahydrofuran (10 mL). The filtrate was evaporated then re-dissolvedwith ethyl acetate (50 mL). The solution was washed with water (50 mL).The water layer was back extracted with ethyl acetate (50 mL). Thecombined organics were washed with brine (30 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure to give acrude residue which was purified by silica gel chromatography (gradientfrom 0-20% ethyl acetate in iso-hexanes) to afford compound 1c. ¹H NMR(400 MHz, CDCl₃) δ 7.28 (d, J=16.6 Hz, 1H), 7.00 (s, 2H), 5.84 (d,J=16.6 Hz, 1H), 2.39 (s, 6H), 1.37 (s, 12H). LCMS (m/z) 284.3 [M+H],Tr=2.85 min (LCMS method 2).

Step 4: Synthesis of(E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 1)

A mixture of compound 1a (50 mg, 0.15 mmol), compound 1c (129 mg, 0.45mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II),complex with dichloromethane (100 mg, 0.12 mmol), potassium carbonate(64 mg, 0.45 mmol), and copper (I) acetate (19 mg, 0.15 mmol) in dryN,N-dimethylformamide (5 mL) was purged with argon and heated at 100° C.for 15 hours. Solvent was removed under reduced pressure and crudemixture was subjected to silica gel chromatography (gradient from 0-30%ethyl acetate in iso-hexanes). The crude product was then re-purified onHPLC (preparative column Phenomenex Gemini 10 micron C18, 250×21.2 mm,10 mL/min, gradient from 10-100% acetonitrile in water) to afford thetitle compound 1. ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.50 (s,1H), 8.09 (d, J=7.8 Hz, 1H), 7.70-7.87 (m, 4H), 7.63 (t, J=7.8 Hz, 1H),7.61 (s, 2H), 7.40 (d, J=8.8 Hz, 2H), 6.62 (d, J=16.7 Hz, 1H), 1.94 (s,6H). HRMS: (ESI+) calculated for C₂₆H₂₀N₅ [M+H] 402.17132, found402.17126. LCMS (m/z) 402.2 [M+H], Tr=4.91 min (LCMS method 1).

Example 2(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound2

Step 1: Synthesis of(E)-3-(4-(4-amino-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 2a)

A mixture of 8-bromo-2-chloroquinazolin-4-amine (129 mg, 0.5 mmol, ArkPharm Inc, AK-28702), compound 1c (184 mg, 0.65 mmol), potassiumphosphate tribasic (159 mg, 0.75 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (65 mg,0.10 mmol) was dissolved in N,N-dimethylformamide:water mixture (85:15,40 mL) under argon. The reaction was heated to 80° C. for 30 minutes.The reaction mixture was cooled down to room temperature and dilutedwith water and ethyl acetate. The organic layer was separated and washedtwice with brine, dried over magnesium sulfate, 0.5 volume equivalent ofhexane added and this mixture was filtered through a 2 cm layer ofsilica gel which was washed with additional ethyl acetate. Combinedorganics were concentrated down under reduced pressure and the residuewas treated with diethyl ether in a sonic bath. The solid product wasfiltered off and washed twice with diethyl ether and once with hexane toafford the title compound 2a. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (bs, 2H),8.28 (dd, J=8.1, 1.6 Hz, 1H), 7.66-7.52 (m, 3H), 7.43 (s, 2H), 6.46 (d,J=16.7 Hz, 1H), 1.86 (s, 6H). LCMS (m/z) 335.2 [M+H], Tr=2.48 min (LCMSmethod 2).

Step 2: Synthesis of(E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 2)

A mixture of compound 2a (100 mg, 0.30 mmol), 4-cyanoaniline (46 mg,0.388 mmol, Sigma-Aldrich) and hydrogen chloride solution in 1,4-dioxane(4M, 7 μL, 0.03 mmol) in dry N-methyl-2-pyrrolidone (2 mL) was heated at120° C. for 2 hours. The reaction mixture was cooled down to roomtemperature and triethylamine (0.1 mL, 0.72 mmol) was added. After 15minutes, water (5 mL) was added and the solid product was filtered offand washed with water. The crude residue was taken up in a mixture ofdichloromethane and diethyl ether (1:1, 5 mL) and then treated in asonic bath for 3 minutes. The solid compound was filtered off and washedwith diethyl ether (5 mL) to afford the title compound 2. ¹H NMR (400MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.18 (dd, J=8.2, 1.5 Hz, 1H), 7.74 (d,J=16.7 Hz, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.51 (s, 2H), 7.48 (dd, J=7.1,1.3 Hz, 1H), 7.34 (dd, J=8.2, 7.1 Hz, 1H), 7.26 (d, J=8.9 Hz, 2H), 6.54(d, J=16.7 Hz, 1H), 1.91 (s, 6H). HRMS: (ESI+) calculated for C₂₆H₂₁N₆[M+H] 417.1822, found 417.1820. LCMS (m/z) 417.2 [M+H], Tr=4.68 min(LCMS method 1).

Example 3(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methoxybenzonitrile—Compound3

Step 1: Synthesis of4-((4-amino-8-bromoquinazolin-2-yl)amino)-2-methoxybenzonitrilehydrochloride (Compound 3a)

A mixture of 8-bromo-2-chloroquinazolin-4-amine (259 mg, 1 mmol, ArkPharm Inc, AK-28702) and 4-amino-2-methoxybenzonitrile (222 mg, 1.5mmol, Ark Pharm Inc, AK-77827) in isopropanol (7 mL) was heated inmicrowave at 180° C. for 8 hours. The reaction mixture was cooled downto room temperature and the solid product was filtered off and washedwith cold isopropanol and then with diethyl ether and hexane to affordthe compound 3a as the HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (d,J=8.1 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.42 (dd,J=8.6, 1.9 Hz, 1H), 7.37-7.04 (m, 5H), 3.99 (s, 3H). LCMS (m/z) 370.3[M+H], Tr=2.43 min (LCMS method 2).

Step 2: Synthesis of(E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methoxybenzonitrile(Compound 3)

A mixture of compound 3a (50 mg, 0.14 mmol), compound 1c (76 mg, 0.27mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II),complex with dichloromethane (33 mg, 0.04 mmol), potassium phosphatetribasic (86 mg, 0.41 mmol), and copper (I) acetate (2 mg, 0.01 mmol) indry N,N-dimethylformamide (5 mL) was purged with argon and heated at120° C. for 3 hours. The reaction mixture was cooled down to roomtemperature and diluted with water and ethyl acetate. The organic layerwas separated and washed twice with brine, dried over magnesium sulfate,1 volume equivalent of hexane added and this mixture was filteredthrough a 3 cm layer of silica gel which was washed with additionalethyl acetate. Combined organics were concentrated down under reducedpressure and the crude mixture was subjected to silica gelchromatography (gradient from 5-50% ethyl acetate in iso-hexanes).Product was then re-purified by reverse phase chromatography (5-100%acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFAsalt of compound 3. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (bs, 1H), 7.74-7.65(m, 2H), 7.62-7.42 (m, 5H), 7.30 (d, J=9.0 Hz, 2H), 7.26-6.95 (m, 1H),6.53 (d, J=17.0 Hz, 1H), 3.41 (s, 3H), 1.93 (s, 6H). LCMS (m/z) 447.4[M+H], Tr=2.39 min (LCMS method 2).

Example 4(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)benzonitrile—Compound4

Step 1: Synthesis of4-((8-bromo-6-fluoroquinazolin-2-yl)amino)benzonitrile (Compound 4a)

A mixture of 8-bromo-2-chloro-6-fluoroquinazoline (500 mg, 1.91 mmol,Ark Pharm Inc, AK-93358) and 4-aminobenzonitrile (250 mg, 2.12 mmol,Sigma-Aldrich) in dry N-methylpyrrolidone was heated in microwave at200° C. for 5 hours. The reaction mixture was cooled down to roomtemperature and subjected to silica gel chromatography (gradient from5-50% ethyl acetate in iso-hexanes). to afford the title compound 4a. ¹HNMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H), 9.37 (s, 1H), 8.32 (d, J=8.7 Hz,2H), 8.26 (dd, J=8.5, 2.7 Hz, 1H), 7.86 (dd, J=8.5, 2.7 Hz, 1H), 7.78(d, J=8.7 Hz, 2H). LCMS (m/z) 343.0 [M+H], Tr=4.72 min (LCMS method 1).

Step 2: Synthesis of(E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)benzonitrile(Compound 4)

A mixture of compound 4a (50 mg, 0.14 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (40 mg, 0.16mmol), potassium acetate (60 mg, 0.61 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (50 mg, 0.061 mmol) in dry N,N-dimethylformamide (5mL) was purged with argon and heated at 100° C. for 1 hour. A mixture ofcompound 1b (33 mg, 0.14 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (50 mg, 0.061 mmol)and potassium carbonate (90 mg, 0.65 mmol) was added to the reactionmixture. The reaction mixture was heated to 100° C. for 5 hours, cooleddown to room temperature, concentrated down under reduced pressure andsubjected to silica gel chromatography (gradient from 5-50% ethylacetate in iso-hexanes). The crude product was then re-purified on HPLC(preparative column Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10mL/min, gradient from 10-100% acetonitrile in water) to afford the titlecompound 4. ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 7.92-7.86 (m, 1H),7.82-7.76 (m, 2H), 7.72 (s, 1H), 7.68 (d, J=8.9 Hz, 2H), 7.58 (s, 2H),7.36 (d, J=8.9 Hz, 2H), 6.60 (d, J=16.7 Hz, 1H), 1.92 (s, 6H). LCMS(m/z) 420.1 [M+H], Tr=4.85 min (LCMS method 1).

Example 5(E)-4-((8-(4-(2-Cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile-Compound5 (Mixture E/Z=4/1)

Step 1: Synthesis of4-((8-(2,6-difluoro-4-formylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 5a)

A mixture of compound 1a (40 mg, 0.12 mmol),3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(66 mg, 0.24 mmol, Sigma-Aldrich), and potassium fluoride (24 mg, 0.4mmol) in a tetrahydrofuran/water mixture (10:1, 10 mL) was purged withargon and tris(dibenzylideneacetone)palladium(0) (68 mg, 0.07 mmol) wasadded followed by tri-tert-butylphosphine (36 μL, 0.14 mmol). Thismixture was heated at 80° C. for 4 hours. The solvent was removed underreduce pressure and the residue was purified by silica gelchromatography (gradient from 20-80% ethyl acetate in iso-hexanes) toafford the title compound 5a. ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H),10.15 (s, 1H), 9.51 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.03 (d, J=7.0 Hz,1H), 7.90 (d, J=6.9 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 7.67-7.58 (m, 1H),7.53 (d, J=8.8 Hz, 2H). LCMS (m/z) 387.1 [M+H], Tr=4.67 min (LCMS method1).

Step 2: Synthesis of(E)-4-((8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile(Compound 5) (Mixture E/Z=4/1)

Cesium carbonate (1.5 g, 4.6 mmol) was added to a solution of compound5a (70 mg, 0.18 mmol) and diethyl (cyanomethyl)phosphonate (32 μL, 0.2mmol) in dry dichloromethane (25 mL) and the solvent was slowly removedunder reduced pressure at 30° C. The resulting reaction mixture wasallowed to stand overnight at room temperature. Dichloromethane wasadded to the residue and the solids were filtered off. The solvent wasremoved under reduced pressure and the residue was purified by HPLC(preparative column Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10mL/min, gradient from 10-100% acetonitrile in water) to afford the titlecompound 5 as a mixture of E/Z isomers 4/1. ¹H NMR for the E isomer (400MHz, DMSO-d₆) δ 10.54 (s, 1H), 9.49 (s, 1H), 8.16-8.12 (m, 1H), 8.0 (d,J=7.3 Hz, 1H), 7.87-7.83 (m, 3H), 7.73 (d, J=8.0 Hz, 2H), 7.63-7.58 (m,1H), 7.56-7.52 (m, 2H), 6.81 (d, J=16.7 Hz, 1H). LCMS (m/z) 410.1 [M+H],Tr=4.76 min (LCMS method 1).

Example 6(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrile—Compound6

Step 1: Synthesis of8-bromo-2-chloro-N-(cyclopropylmethyl)quinazolin-4-amine (Compound 6a)

Cyclopropylmethanamine (95 μL, 1.1 mmol) and N-ethyldiisopropylamine(0.35 mL, 2 mmol) were added to a solution of8-bromo-2,4-dichloroquinazoline (278 mg, 1 mmol, Ark Pharm Inc.,AK-28703) in isopropanol (5 mL). The reaction mixture was stirred atroom temperature for 30 minutes. The solid product was filtered off andwashed with water (2×5 mL) and pentane (3×5 mL) to give the titlecompound 6a. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.30 (dd, J=8.3Hz, J=1.3 Hz, 1H), 8.12 (dd, J=7.7 Hz, J=1.3 Hz, 1H), 7.44 (t, J=8.0 Hz,1H), 3.41-3.35 (m, 2H), 1.23-1.11 (m, 1H), 0.52-0.45 (m, 2H), 0.34-0.28(m, 2H). HRMS: (ESI+) calculated for C₁₂H₁₂N₃BrCl [M+H] 311.9898, found311.9898. LCMS (m/z) 312.0 [M+H], Tr 4.59 min (LCMS method 1).

Step 2: Synthesis of4-((8-bromo-4-((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrilehydrochloride (Compound 6b)

A mixture of compound 6a (156 mg, 0.5 mmol) and 4-aminobenzonitrile (71mg, 0.6 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated inmicrowave at 180° C. for 2 hours. The reaction mixture was cooled downto room temperature and the solid product was filtered off and washedtwice with cold isopropanol and then three times with pentane to affordthe compound 6b as the HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (d,J=7.7 Hz, 1H), 8.15-7.99 (m, 3H), 7.81 (d, J=8.4 Hz, 2H), 7.33 (t, J=7.9Hz, 1H), 3.53-3.45 (m, 2H), 1.30-1.17 (m, 1H), 0.54-0.48 (m, 2H),0.37-0.32 (m, 2H). HRMS: (ESI+) calculated for C₁₉H₁₇N₅Br [M+H]394.0662, found 394.0661. LCMS (m/z) 394.0 [M+H], Tr 4.29 min (LCMSmethod 1).

Step 3: Synthesis of(E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrile(Compound 6)

A mixture of compound 6b (65 mg, 0.15 mmol), compound 1c (64 mg, 0.23mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II),complex with dichloromethane (37 mg, 0.05 mmol) and potassium carbonate(104 mg, 0.75 mmol) in the mixture of 1,4-dioxane and water (10:1, 5 mL)was purged with argon and heated at 100° C. for 1 hour. Solvents wereremoved under reduced pressure and the residue was purified by silicagel chromatography (gradient from 20-40% ethyl acetate in iso-hexanes)to afford the title compound 6. ¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s,1H), 8.39 (t, J=5.6 Hz, 1H), 8.24-8.13 (m, 2H), 7.74-7.69 (m, 2H), 7.51(s, 2H), 7.46 (dd, J=7.2 Hz, J=1.4 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.26(d, J=8.9 Hz, 2H), 6.54 (d, J=16.7 Hz, 1H), 3.47-3.43 (m, 2H), 1.90 (s,6H), 1.30-1.21 (m, 1H), 0.53-0.47 (m, 2H), 0.35-0.30 (m, 2H). HRMS:(ESI+) calculated for C₃₀H₂₇N₆ [M+H] 471.2292, found 471.2292. LCMS(m/z) 471.2 [M+H], Tr 4.05 min (LCMS method 1).

Example 7(E)-4-((4-(Butylamino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound7

Step 1: Synthesis of 8-bromo-N-butyl-2-chloroquinazolin-4-amine(Compound 7a)

n-Butylamine (109 μL, 1.1 mmol) and N-ethyldiisopropylamine (0.35 mL, 2mmol) were added to a solution of 8-bromo-2,4-dichloroquinazoline (278mg, 1 mmol, Ark Pharm Inc., AK-28703) in isopropanol (5 mL). Thereaction mixture was stirred at room temperature for 30 minutes. Thesolid product was filtered off and washed with water (2×5 mL) andpentane (3×5 mL) to give the title compound 7a. ¹H NMR (400 MHz,DMSO-d₆) δ 8.87 (s, 1H), 8.27 (dd, J=8.3 Hz, J=1.2 Hz, 1H), 8.12 (dd,J=7.7 Hz, J=1.2 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 3.55-3.48 (m, 2H),1.66-1.57 (m, 2H), 1.41-1.31 (m, 2H), 0.92 (t, J=7.3 Hz, 3H). HRMS:(ESI+) calculated for C₁₂H₁₄N₃BrCl [M+H] 314.0054, found 314.0055. LCMS(m/z) 314.0 [M+H], Tr 4.76 min (LCMS method 1).

Step 2: Synthesis of4-((8-bromo-4-(butylamino)quinazolin-2-yl)amino)benzonitrilehydrochloride (Compound 7b)

A mixture of compound 7a (157 mg, 0.5 mmol) and 4-aminobenzonitrile (71mg, 0.6 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated inmicrowave at 180° C. for 2 hours. The reaction mixture was cooled downto room temperature and the solid product was filtered off and washedtwice with cold isopropanol and then three times with pentane to affordthe compound 7b as the HCl salt. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d,J=7.8 Hz, 1H), 8.21-7.79 (m, 3H), 7.79 (d, J=8.3 Hz, 2H), 7.29 (t, J=7.8Hz, 1H), 3.65-3.63 (m, 2H), 1.74-1.59 (m, 2H), 1.43-1.33 (m, 2H), 0.92(t, J=7.4 Hz, 3H). HRMS: (ESI+) calculated for C₁₉H₁₉N₅Br [M+H]396.0818, found 396.0816. LCMS (m/z) 396.1 [M+H], Tr 4.34 min (LCMSmethod 1).

Step 3: Synthesis of(E)-4-((4-(butylamino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 7)

A mixture of compound 7b (65 mg, 0.15 mmol), compound 1c (64 mg, 0.23mmol), [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II),complex with dichloromethane (37 mg, 0.05 mmol) and potassium carbonate(104 mg, 0.75 mmol) in the mixture of 1,4-dioxane and water (10:1, 5 mL)was purged with argon and heated at 100° C. for 1 hour. Solvents wereremoved under reduced pressure and the residue was purified by silicagel chromatography (gradient from 20-40% ethyl acetate in iso-hexanes)to afford the title compound 7. ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s,1H), 8.25-8.16 (m, 2H), 7.78-7.69 (m, 3H), 7.51 (s, 2H), 7.46 (dd, J=7.1Hz, J=1.3 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 7.27 (d, J=8.9 Hz, 2H), 6.54(d, J=16.7 Hz, 1H), 3.63-3.51 (m, 2H), 1.90 (s, 6H), 1.72-1.65 (m, 2H),1.46-1.38 (m, 2H), 0.95 (t, J=7.4 Hz, 3H). MS-ESI⁺ m/z (%): 473 (100,M+H⁺), 495 (20, M+Na⁺); HRMS: (ESI+) calculated for C₃₀H₂₉N₆ [M+H]473.2448, found 473.2448. LCMS (m/z) 473.3 [M+H], Tr 4.14 min (LCMSmethod 1).

Example 8(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile—Compound8 (Mixture E/Z=3/2)

Step 1: Synthesis of4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile (Compound 8a)

A mixture of 8-bromo-2-chloroquinazolin-4-amine (259 mg, 1 mmol, ArkPharm Inc, AK-28702) and 4-aminobenzonitrile (130 mg, 1.1 mmol,Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 160° C.for 3 hours. The reaction mixture was cooled down to room temperatureand the solid product was filtered off and washed with cold isopropanoland then with diethyl ether to afford the compound 2a. ¹H NMR (400 MHz,DMSO-d₆) δ 9.74 (s, 1H), 8.35 (d, J=8.8 Hz, 2H), 8.16 (d, J=8.0 Hz, 1H),8.01 (d, J=7.5 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.16 (t, J=7.8 Hz, 1H).HRMS: (ESI+) calculated for C₁₅H₁₁N₅Br [M+H] 340.0192, found 340.0192.LCMS (m/z) 340.0 [M+H], Tr=4.06 min (LCMS method 1).

Step 2: Synthesis of4-((4-amino-8-(2,6-difluoro-4-formylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 8b)

A mixture of compound 8a (120 mg, 0.36 mmol),3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(285 mg, 1.06 mmol, Sigma-Aldrich), and potassium fluoride (102 mg, 1.76mmol) in a tetrahydrofuran/water mixture (10:1, 30 mL) was purged withargon and tris(dibenzylideneacetone)palladium(0) (195 mg, 0.213 mmol)was added followed by tri-tert-butylphosphine (103 μL, 0.43 mmol). Themixture was heated at 80° C. for 4 hours. The solvent was removed underreduce pressure and the residue was purified by silica gelchromatography (gradient from 20-80% ethyl acetate in iso-hexanes) toafford the title compound 8b. ¹H NMR (400 MHz, DMSO-d₆) δ 10.12 (s, 1H),9.56 (s, 1H), 8.29 (dd, J=8.2 Hz, J=1.1 Hz, 2H), 7.87-7.73 (m, 6H),7.44-7.34 (m, 3H). LCMS (m/z) 401.9 [M+H], Tr=4.28 min (LCMS method 1).

Step 3: Synthesis of(E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile(Compound 8) (Mixture E/Z=3/2)

Cesium carbonate (2.5 g, 7.69 mmol) was added to a solution of compound8b (74 mg, 0.18 mmol) and diethyl (cyanomethyl)phosphonate (30 μL, 0.18mmol) in dry dichloromethane (25 mL) and the solvent was slowly removedunder reduced pressure at 30° C. The resulting reaction mixture wasallowed to stand overnight at room temperature. Dichloromethane wasadded to the residue and the solids were filtered off. The solvent wasremoved under reduced pressure and the residue was purified by HPLC(preparative column Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10mL/min, gradient from 10-100% acetonitrile in water) to afford the titlecompound 8 as a mixture of E/Z isomers 3/2. ¹H NMR for the E isomer (400MHz, DMSO-d₆) δ 9.54 (s, 1H), 8.29-8.24 (m, 2H), 7.84 (d, J=2.4 Hz, 1H),7.82-7.78 (m, 2H), 7.72 (d, J=7.3, 2H), 7.66 (d, J=7.8 Hz, 2H),7.43-7.39 (m, 2H), 7.38-7.33 (m, 1H), 6.77 (d, J=16.7 Hz, 1H). LCMS(m/z) 424.9 [M+H], Tr=3.46 min (LCMS method 1).

Example 9(E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)picolinonitrile—Compound9

Step 1: Synthesis of5-((4-amino-8-bromoquinazolin-2-yl)amino)picolinonitrile (Compound 9a)

A mixture of 8-bromo-2-chloroquinazolin-4-amine (500 mg, 1.9 mmol, ArkPharm Inc, AK-28702) and 5-aminopicolinonitrile (253 mg, 2.1 mmol, ArkPharm Inc, AK-26123) in isopropanol (10 mL) was heated under argon inmicrowave at 180° C. for 8 hours. The reaction mixture was cooled downto room temperature and the solid product was filtered off and washedwith cold isopropanol and then with diethyl ether and hexane to affordthe compound 9a. ¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 9.35 (dd,J=2.6, 0.7 Hz, 1H), 8.85 (dd, J=8.7, 2.6 Hz, 1H), 8.17 (dd, J=8.2, 1.3Hz, 1H), 8.03 (dd, J=7.6, 1.3 Hz, 1H), 7.95-7.91 (m, 2H), 7.23-7.10 (m,2H). LCMS (m/z) 343.2 [M+H], Tr=2.31 min (LCMS method 2).

Step 2: Synthesis of(E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)picolinonitrile(Compound 9)

Compound 9a (150 mg, 0.44 mmol), compound 1c (498 mg, 1.76 mmol),potassium phosphate tribasic (560 mg, 2.64 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (57 mg,0.09 mmol) were dissolved in N,N-dimethylformamide:water mixture (85:15,25 mL) under argon. The reaction was heated at 90° C. for 1 hour. Thereaction mixture was cooled down to room temperature and diluted withwater and ethyl acetate. The organic layer was separated. The waterlayer was washed with additional ethyl acetate. Combined organics werewashed twice with brine and dried over magnesium sulfate. Solvents wereremoved under reduced pressure and the residue was purified by silicagel chromatography (gradient from 0-40% ethyl acetate and methanol (4/1)in iso-hexanes). Solvents were removed under reduced pressure and thesolid residue was treated with the mixture of hexane/diethyl ether (5:1)in the sonic bath for 5 minutes, filtered off and washed with hexane toafford the title compound 9. ¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H),8.74 (d, J=2.5 Hz, 1H), 8.24-8.15 (m, 2H), 7.72 (d, J=16.7 Hz, 1H), 7.49(d, J=7.6 Hz, 3H), 7.40-7.30 (m, 2H), 6.51 (d, J=16.7 Hz, 1H), 1.90 (s,6H). LCMS (m/z) 418.3 [M+H], Tr=2.47 min (LCMS method 2).

Example 10(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile—Compound10

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile(Compound 10)

Compound 2a (820 mg, 2.45 mmol), 6-aminonicotinonitrile (875 mg, 7.35mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (2.53 g, 19.6mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (142mg, 0.25 mmol) and palladium (II) acetate (55 mg, 0.25 mmol) werecombined under argon in N-methyl-2-pyrrolidone (40 mL). The reaction washeated at 120° C. in a sealed vessel for 4 hours. The reaction mixturewas cooled down to room temperature and diluted with water and ethylacetate. The organic layer was separated and washed twice with brine,dried over magnesium sulfate, 0.05 volume equivalent of hexane added andthis mixture was filtered through a 2 cm layer of silica gel which waswashed with additional ethyl acetate. Combined organics wereconcentrated down under reduced pressure. The crude residue was treatedwith diethyl ether/dichloromethane mixture (1:1) in the sonic bath for 5minutes. The solid compound was filtered off and washed twice withdiethyl ether and once with hexane to afford the title compound 10. ¹HNMR (400 MHz, DMSO-d₆) δ 9.58 (s, 1H), 8.57 (dd, J=2.4, 0.8 Hz, 1H),8.20 (dd, J=8.3, 1.4 Hz, 1H), 7.95 (dd, J=9.0, 0.8 Hz, 1H), 7.73 (d,J=16.7 Hz, 1H), 7.55-7.51 (m, 3H), 7.44-7.36 (m, 2H), 6.53 (d, J=16.7Hz, 1H), 1.90 (s, 6H). LCMS (m/z) 418.3 [M+H], Tr=1.82 min (LCMS method2).

Example 11(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyridazine-3-carbonitrile—Compound11

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyridazine-3-carbonitrile(Compound 11)

Compound 2a (20 mg, 0.06 mmol), 6-aminopyridazine-3-carbonitrile (22 mg,0.18 mmol, Matrix Scientific, 112287), N,N-diisopropylethylamine (62 mg,0.47 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) werecombined under argon in N-methyl-2-pyrrolidone (2 mL). The reaction washeated at 120° C. in a sealed vessel for 1 hour. The reaction mixturewas cooled down to room temperature and purified by HPLC reverse phasechromatography (0-100% acetonitrile in water with 0.1% trifluoroaceticacid) to afford the TFA salt of compound 11. ¹H NMR (400 MHz, DMSO-d₆) δ8.35 (bs, 1H), 8.09 (bs, 1H), 7.78-7.39 (m, 6H), 6.54 (d, J=16.7 Hz,1H), 1.93 (s, 6H). LCMS (m/z) 419.3 [M+H], Tr=2.03 min (LCMS method 2).

Example 12(E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyrazine-2-carbonitrile—Compound12

Synthesis of(E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyrazine-2-carbonitrile(Compound 12)

Compound 2a (20 mg, 0.06 mmol), 5-aminopyrazine-2-carbonitrile (22 mg,0.18 mmol, Ark Pharm Inc, AK-21935), N,N-diisopropylethylamine (62 mg,0.47 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) werecombined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction washeated at 120° C. in a sealed vessel for 3 hours. The reaction mixturewas cooled down to room temperature and purified by reverse phasechromatography (0-100% acetonitrile in water with 0.1% trifluoroaceticacid) to afford the TFA salt of compound 12. ¹H NMR (400 MHz, DMSO-d₆) δ8.98 (bs, 1H), 8.36 (bs, 1H), 7.85-7.28 (m, 6H), 6.59 (d, J=15.6 Hz,1H), 1.94 (s, 6H). LCMS (m/z) 419.3 [M+H], Tr=1.89 min (LCMS method 2).

Example 13(E)-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile—Compound13

Step 1: Synthesis of(E)-3-(4-(2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 13a)

A mixture of 8-bromo-2-chloroquinazoline (500 mg, 2.05 mmol, Ark PharmInc, AK-27609), compound 1c (776 mg, 2.67 mmol), potassium phosphatetribasic (633 mg, 3.08 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (134 mg,0.21 mmol) was dissolved in N,N-dimethylformamide:water mixture (85:15,10 mL) under argon. The reaction was heated to 50° C. for 2 hours. Thereaction mixture was cooled down to room temperature and diluted withwater and ethyl acetate. The organic layer was separated and washedtwice with brine, dried over magnesium sulfate, 0.5 volume equivalent ofhexane added and this mixture was filtered through a 2 cm layer ofsilica gel which was washed with additional hexane/ethyl acetate mixture(1/1). Combined organics were concentrated down under reduced pressureand the residue was treated with diethyl ether in a sonic bath. Thesolid product was filtered off and washed twice with diethyl ether andonce with hexane to afford the title compound 13a. ¹H NMR (400 MHz,DMSO-d₆) δ 9.70 (s, 1H), 8.30 (dd, J=7.1, 2.5 Hz, 1H), 7.99-7.84 (m,2H), 7.66 (d, J=16.7 Hz, 1H), 7.49 (s, 2H), 6.50 (d, J=16.7 Hz, 1H),1.85 (s, 6H). LCMS (m/z) 320.1 [M+H], Tr=1.40 min (LCMS method 3).

Step 2: Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile(Compound 13)

Compound 13a (508 mg, 1.60 mmol), 6-aminonicotinonitrile (567 mg, 4.77mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (1.64 g, 12.71mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (93 mg,0.16 mmol) and palladium (II) acetate (36 mg, 0.16 mmol) were combinedunder argon in N-methyl-2-pyrrolidone (10 mL). The reaction was heatedat 80° C. in a sealed vessel for 30 minutes. The reaction mixture wascooled down to room temperature and diluted with water and ethylacetate. The organic layer was separated and washed twice with brine,dried over magnesium sulfate, 0.5 volume equivalent of hexane added andthis mixture was filtered through a 2 cm layer of silica gel which waswashed with additional hexane/ethyl acetate mixture (1/1). Combinedorganics were concentrated down under reduced pressure. The cruderesidue was treated with diethyl ether in the sonic bath for 5 minutes.The solid compound was filtered off and washed twice with diethyl etherand once with hexane to afford the title compound 13. ¹H NMR (400 MHz,DMSO-d₆) δ 10.85 (s, 1H), 9.52 (s, 1H), 8.66 (dd, J=2.3, 0.9 Hz, 1H),8.10 (dd, J=8.0, 1.4 Hz, 1H), 7.92 (dd, J=8.9, 0.9 Hz, 1H), 7.85-7.70(m, 2H), 7.65 (dd, J=8.1, 7.1 Hz, 1H), 7.57-7.48 (m, 3H), 6.56 (d,J=16.7 Hz, 1H), 1.89 (s, 6H). LCMS (m/z) 403.2 [M+H], Tr=1.48 min (LCMSmethod 3).

Example 14(E)-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile—Compound14

Step 1:(E)-3-(4-(2-chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 14a)

A mixture of compound 1c (100 mg, 0.35 mmol),8-bromo-2-chloro-6-fluoroquinazoline (100 mg, 0.38 mmol, Ark Pharm Inc,AK-93358), 1,1′-bis(di-tert-butylphosphino)ferrocene palladiumdichloride (50 mg, 0.08 mmol) and potassium phosphate tribasicmonohydrate (200 mg, 0.77 mmol) in N,N-dimethylformamide (3 mL) andwater (0.3 mL) was heated under argon at 80° C. for 30 minutes. Thereaction mixture was evaporated to dryness and the residue was purifiedby silica gel chromatography This was subjected to silica gelchromatography (gradient from 0-100% ethyl acetate in iso-hexanes) toafford compound 14a. LCMS (m/z) 337.9 [M+H], Tr=4.52 min (LCMS method1).

Step 2: Synthesis of(E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile(Compound 14)

Compound 14aa (100 mg, 0.30 mmol), 6-aminonicotinonitrile (200 mg, 1.68mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (0.5 mL, 2.86mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (180mg, 0.31 mmol) and palladium (II) acetate (40 mg, 0.18 mmol) werecombined under argon in N-methyl-2-pyrrolidone (3 mL). The reaction washeated at 100° C. in a sealed vessel for 1 hour. The reaction mixturewas cooled down to room temperature and directly purified by silica gelchromatography (gradient from 60-100% ethyl acetate in iso-hexanes andthen gradient from 0-20% methanol in ethyl acetate) to afford the titlecompound 14. ¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.77 (dd, J=2.3,0.8 Hz, 1H), 8.08-7.99 (m, 1H), 7.99-7.91 (m, 1H), 7.87 (d, J=16.7 Hz,1H), 7.68 (s, 2H), 7.65-7.60 (m, 1H), 7.60-7.53 (m, 1H), 7.36 (d, J=8.2,Hz, 1H), 6.68 (d, J=16.7 Hz, 1H), 2.01 (s, 6H). LCMS (m/z) 420.9 [M+H],Tr=4.62 min (LCMS method 1).

Example 15(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2,4-dimethylnicotinonitrile—Compound15

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2,4-dimethylnicotinonitrile(Compound 15)

Compound 2a (20 mg, 0.06 mmol), 6-amino-2,4-dimethylnicotinonitrile (26mg, 0.18 mmol, Key Organics Ltd, 1X-0933), N,N-diisopropylethylamine(622 mg, 0.48 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4 mg, 0.006mmol) and palladium (II) acetate (1 mg, 0.006 mmol) were combined underargon in N-methyl-2-pyrrolidone (1 mL). The reaction was heated at 120°C. in a sealed vessel for 4 hours. The reaction mixture was cooled downto room temperature and diluted with water and ethyl acetate. Theorganic layer was separated and washed twice with brine, dried overmagnesium sulfate and this solution was filtered through a 2 cm layer ofsilica gel which was washed with additional ethyl acetate. Combinedorganics were concentrated down under reduced pressure. The cruderesidue was treated with diethyl ether in the sonic bath for 5 minutes.The solid compound was filtered off and washed twice with diethyl etherand once with hexane to afford the title compound 15. ¹H NMR (400 MHz,DMSO-d₆) δ 9.56 (bs, 1H), 9.29 (bs, 1H), 8.44 (d, J=8.0 Hz, 1H),7.99-7.47 (m, 5H), 7.41-7.10 (m, 1H), 6.55 (d, J=16.7 Hz, 1H), 2.41 (bs,3H), 1.96 (s, 6H), 1.62 (bs, 3H). LCMS (m/z) 446.4 [M+H], Tr=1.19 min(LCMS method 3).

Example 16(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methylnicotinonitrile—Compound16

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methylnicotinonitrile(Compound 16)

Compound 2a (20 mg, 0.06 mmol), 6-amino-2-methylnicotinonitrile (24 mg,0.18 mmol, Ark Pharm Inc, AK-78835), N,N-diisopropylethylamine (622 mg,0.48 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) werecombined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction washeated at 120° C. in a sealed vessel for 4 hours. The reaction mixturewas cooled down to room temperature and diluted with water and ethylacetate. The organic layer was separated and washed twice with brine,dried over magnesium sulfate and this solution was filtered through a 2cm layer of silica gel which was washed with additional ethyl acetate.Combined organics were concentrated down under reduced pressure. Thecrude residue was treated with diethyl ether in the sonic bath for 5minutes. The solid compound was filtered off and washed twice withdiethyl ether and once with hexane to afford the title compound 16. ¹HNMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H), 9.55 (s, 1H), 9.10 (s, 1H), 8.46(dd, J=8.3, 1.3 Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.89-7.73 (m, 3H), 7.69(s, 2H), 7.32 (d, J=2.2 Hz, 1H), 6.68 (d, J=16.7 Hz, 1H), 2.37 (s, 3H),1.95 (s, 6H). LCMS (m/z) 432.4 [M+H], Tr=1.15 min (LCMS method 3).

Example 17(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-5-methylnicotinonitrile—Compound17

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-5-methylnicotinonitrile(Compound 17)

Compound 2a (20 mg, 0.06 mmol), 6-amino-5-methylnicotinonitrile (24 mg,0.18 mmol, Ark Pharm Inc, AK-25043), N,N-diisopropylethylamine (622 mg,0.48 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) werecombined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction washeated at 120° C. in a sealed vessel for 4 hours. The reaction mixturewas cooled down to room temperature and diluted with water and ethylacetate. The organic layer was separated and washed twice with brine,dried over magnesium sulfate and this solution was filtered through a 2cm layer of silica gel which was washed with additional ethyl acetate.Combined organics were concentrated down under reduced pressure. Thecrude residue was treated with diethyl ether in the sonic bath for 5minutes. The solid compound was filtered off and washed twice withdiethyl ether and once with hexane to afford the title compound 17. ¹HNMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H), 9.55 (s, 1H), 9.10 (s, 1H), 8.46(dd, J=8.3, 1.3 Hz, 1H), 8.25-8.13 (m, 1H), 7.91-7.72 (m, 3H), 7.69 (s,2H), 7.35-7.29 (m, 1H), 6.68 (d, J=16.7 Hz, 1H), 2.37 (s, 3H), 1.95 (s,6H). LCMS (m/z) 432.4 [M+H], Tr=1.19 min (LCMS method 3).

Example 18(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-4-methylnicotinonitrile—Compound18

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-4-methylnicotinonitrile(Compound 18)

Compound 2a (20 mg, 0.06 mmol), 6-amino-4-methylnicotinonitrile (24 mg,0.18 mmol, Ark Pharm Inc, AK-80125), N,N-diisopropylethylamine (622 mg,0.48 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) werecombined under argon in N-methyl-2-pyrrolidone (1 mL). The reaction washeated at 120° C. in a sealed vessel for 4 hours. The reaction mixturewas cooled down to room temperature and diluted with water and ethylacetate. The organic layer was separated and washed twice with brine,dried over magnesium sulfate and this solution was filtered through a 2cm layer of silica gel which was washed with additional ethyl acetate.Combined organics were concentrated down under reduced pressure. Thecrude residue was treated with diethyl ether in the sonic bath for 5minutes. The solid compound was filtered off and washed twice withdiethyl ether and once with hexane to afford the title compound 18. ¹HNMR (400 MHz, DMSO-d₆) δ 11.97 (bs, 1H), 9.55 (bs, 1H), 9.32 (bs, 1H),8.48-8.37 (m, 1H), 7.90-7.62 (m, 5H), 7.52-7.43 (m, 1H), 7.32-7.23 (m,1H), 6.69 (d, J=16.7 Hz, 1H), 2.45 (s, 3H), 1.96 (s, 6H). LCMS (m/z)432.3 [M+H], Tr=1.25 min (LCMS method 3).

Example 19(E)-4-((4-Amino-6-chloro-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound19

Step 1: Synthesis of 2-amino-3-bromo-5-chlorobenzoic Acid (Compound 19a)

A mixture of 2-amino-5-chlorobenzoic acid (5 g, 29 mmol, Ark Pharm Inc,AK-26989) and N-bromosuccinimide (5.4 g, 30 mmol) inN,N-dimethylformamide (100 mL) was stirred at room temperature for 14hours. The reaction mixture was poured into water (400 mL) and productwas extracted with diethylether (400 mL). The organic phase was washedwith brine (200 mL), dried over sodium sulfate, filtered andconcentrated down under reduced pressure to afford the title compound19a. LCMS (m/z) 250.0 [M+H], Tr=4.05 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-chloroquinazoline-2,4(1H,3H)-dione(Compound 19b)

A mixture of compound 19a (5.3 g, 21 mmol) and urea (30 g, 500 mmol) washeated at 200° C. for 3 hours. The reaction mixture was cooled down,diluted with methanol (100 mL) and the product was filtered off. Thesolid was washed with water (50 mL) and methanol (50 mL) to afford thetitle compound 19b. LCMS (m/z) 275.0 [M+H], Tr=3.32 min (LCMS method 1).

Step 3: Synthesis of 8-bromo-2,6-dichloroquinazolin-4-amine (Compound19c)

A mixture of compound 19b (5.3 g, 21 mmol), phosphorus(V) oxychloride(15 mL) and N,N-dimethylformamide (3 drops) was heated at 120° C. for 14hours. The reaction mixture was cooled down, poured into water (200 mL)and the product was filtered off. The solid was dried in vacuo for 2hours, suspended in saturated ethanolic solution of ammonia (50 mL) andstirred at room temperature for 14 hours. The solid product was filteredoff to afford the title compound 19c. ¹H NMR (400 MHz, DMSO-d₆) δ 8.65(s, 2H), 8.47 (d, J=2.2 Hz, 1H), 8.25 (d, J=2.2 Hz, 1H). LCMS (m/z)291.9 [M+H], Tr=3.86 min (LCMS method 1).

Step 4: Synthesis of(E)-3-(4-(4-amino-2,6-dichloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 19d)

A mixture of compound 19c (146 mg, 0.5 mmol), compound 1c (170 mg, 0.6mmol), potassium phosphate tribasic monohydrate (230 mg, 1 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (65 mg, 0.1 mmol) was dissolved in a mixture ofN,N-dimethylformamide and water (10:1, 5.5 mL) under argon and thismixture was stirred at 80° C. for 30 minutes. The product was isolatedby silica gel chromatography (gradient from 80-100% ethyl acetate iniso-hexanes) to afford the title compound 19d. LCMS (m/z) 369.0 [M+H],Tr=4.30 (LCMS method 1).

Step 5: Synthesis of(E)-4-((4-amino-6-chloro-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 19)

A mixture of compound 19d (85 mg, 0.23 mmol), 4-aminobenzonitrile (33mg, 0.28 mmol, Sigma-Aldrich), palladium(II) acetate (10 mg, 0.046 mmol)and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (27 mg,0.046 mmol) was dissolved in N-methyl-2-pyrrolidone (2 mL) under argon.N,N-Diisopropylethylamine (174 μL, 1 mmol) was then added via syringeand the reaction mixture was stirred at 100° C. for 1 hour. The productwas isolated by silica gel flash chromatography (gradient from 40-60%ethyl acetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep pre-packed column, gradient 5-100%,acetonitrile in water) to afford the title compound 19. ¹H NMR (400 MHz,DMSO-d₆) δ 9.55 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 7.74 (d, J=16.7 Hz,1H), 7.66 (d, J=8.9 Hz, 2H), 7.55 (d, J=2.3 Hz, 1H), 7.52 (s, 2H),7.40-7.35 (m, 2H), 7.26 (d, J=8.9 Hz, 2H), 6.55 (d, J=16.7 Hz, 1H), 1.93(s, 6H). LCMS (m/z) 451.2 [M+H], Tr=4.25 min (LCMS method 1).

Example 20(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile—Compound20

Step 1: Synthesis of 2-amino-3-bromo-5-fluorobenzoic Acid (Compound 20a)

A mixture of 2-amino-5-fluorobenzoic acid (10 g, 65 mmol, Ark Pharm Inc,AK-35193) and N-bromosuccinimide (12 g, 67 mmol) inN,N-dimethylformamide (100 mL) was stirred at room temperature for 14hours. The reaction mixture was poured into water (500 mL), the solidproduct was filtered off and washed with water to afford the titlecompound 20a. LCMS (m/z) 233.7 [M+H], Tr=3.75 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-fluoroquinazoline-2,4(1H,3H)-dione(Compound 20b)

A mixture of compound 20a (12 g, 51 mmol) and urea (20 g, 333 mmol) washeated at 200° C. for 3 hours. The reaction mixture was cooled down anddiluted with water (100 mL). The solid product was filtered off andwashed with methanol (50 mL) to afford the title compound 20b. LCMS(m/z) 259.0 [M+H], Tr=3.23 min (LCMS method 1).

Step 3: Synthesis of 8-bromo-2-chloro-6-fluoroquinazolin-4-amine(Compound 20c)

A mixture of compound 20b (3 g, 20 mmol), phosphorus(V) oxychloride (20mL) and N,N-dimethylformamide (3 drops) was heated at 120° C. for 14hours. The reaction mixture was cooled down, poured into ice watermixture (200 mL) and the solid product was filtered off. The solid wasdried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room temperature for 14 hours. Thereaction mixture was evaporated to dryness and the solid residue wassuspended in water. The solid product was filtered off to afford thetitle compound 20c. ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.46 (s,1H), 8.19 (dd, J=8.3, 2.7 Hz, 1H), 8.13 (dd, J=9.2, 2.7 Hz, 1H). LCMS(m/z) 275.7 [M+H], Tr=3.74 min (LCMS method 1).

Step 4: Synthesis of(E)-3-(4-(4-amino-2-chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 20d)

A mixture of compound 20c (276 mg, 1 mmol), compound 1c (340 mg, 1.2mmol), potassium phosphate tribasic monohydrate (460 mg, 2 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (65 mg, 0.1 mmol) was dissolved in a mixture ofN,N-dimethylformamide and water (10:1, 11 mL) under argon and thismixture was stirred at 80° C. for 30 minutes. The product was isolatedby silica gel chromatography (gradient from 80-100% ethyl acetate iniso-hexanes) to afford the title compound 20d. LCMS (m/z) 352.9 [M+H],Tr=4.12 min (LCMS method 1).

Step 5: Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile(Compound 20)

A mixture of compound 20d (176 mg, 0.5 mmol), 6-aminonicotinonitrile(178 mg, 1.5 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (22mg, 0.1 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1mmol) was dissolved in N-methyl-2-pyrrolidone (5 mL) under argon.N,N-Diisopropylethylamine (348 μL, 2 mmol) was then added via syringeand the reaction mixture was stirred at 100° C. for 1 hour. The productwas isolated by silica gel chromatography (gradient from 40-100% ethylacetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%,acetonitrile in water with 0.1% TFA) to afford the title compound 20 asthe TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (bs, 1H), 9.46 (bs, 1H),8.40-8.20 (m, 2H), 8.02-7.84 (m, 1H), 7.82 (d, J=16.6 Hz, 1H), 7.69 (s,2H), 7.51 (bs, 1H), 7.42 (bs, 1H), 6.69 (d, J=16.6 Hz, 1H), 1.98 (s,6H). LCMS (m/z) 435.8 [M+H], Tr=3.45 min (LCMS method 1).

Example 21(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methylquinazolin-2-yl)amino)nicotinonitrile—Compound21

Step 1: Synthesis of 2-amino-3-bromo-5-methylbenzoic Acid (Compound 21a)

A mixture of 2-amino-5-methylbenzoic acid (10 g, 66 mmol, Ark Pharm, IncAK-34555) and N-bromosuccinimide (12 g, 67 mmol) inN,N-dimethylformamide (100 mL) was stirred at room temperature for 14hours. The reaction mixture was poured into water (500 mL) and the solidproduct was filtered off and washed with water to afford the titlecompound 21a. LCMS (m/z) 229.80 [M+H], Tr=3.87 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-methylquinazoline-2,4(1H,3H)-dione(Compound 21b)

A mixture of compound 21a (5 g, 22 mmol) and urea (30 g, 500 mmol) washeated at 200° C. for 3 hours. The reaction mixture was cooled down, anddiluted with water (100 mL). The solid product was filtered off andwashed with methanol (50 mL) and water (50 mL) to afford the titlecompound 21b. LCMS (m/z) 254.7 [M+H], Tr=3.19 min (LCMS method 1).

Step 3: Synthesis of 8-bromo-2-chloro-6-methylquinazolin-4-amine(Compound 21c)

A mixture of compound 21b (5 g, 20 mmol), phosphorus(V) oxychloride (15mL) and N,N-dimethylformamide (3 drops) was heated at 120° C. for 14hours. The reaction mixture was cooled down, poured into ice watermixture (200 mL) and the solid product was filtered off. The solid wasdried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room temperature for 14 hours. The solidproduct was filtered off to afford the title compound 21c. ¹H NMR (400MHz, DMSO-d₆) δ 8.41 (s, 2H), 8.06 (d, J=1.7 Hz, 1H), 8.01 (d, J=1.7 Hz,1H), 2.42 (s, 3H). LCMS (m/z) 271.8 [M+H], Tr=3.65 min (LCMS method 1).

Step 4: Synthesis of(E)-3-(4-(4-amino-2-chloro-6-methylquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 21d)

A mixture of compound 21c (273 mg, 1 mmol), compound 1c (340 mg, 1.2mmol), potassium phosphate tribasic monohydrate (460 mg, 2 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (65 mg, 0.1 mmol) was dissolved in a mixture ofN,N-dimethylformamide and water (10:1, 5.5 mL) under argon and thisreaction mixture was stirred at 80° C. for 30 minutes. The product wasisolated by silica gel chromatography (gradient from 40-100% ethylacetate in iso-hexanes) to afford the title compound 21d. LCMS (m/z)348.9 [M+H], Tr=4.17 min (LCMS method 1).

Step 5: Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methylquinazolin-2-yl)amino)nicotinonitrile(Compound 21)

A mixture of compound 21d (175 mg, 0.5 mmol), 6-aminonicotinonitrile(298 mg, 2.5 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (23mg, 0.1 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1mmol) was dissolved in N-methyl-2-pyrrolidone (5 mL) under argon.N,N-Diisopropylethylamine (435 μL, 2.5 mmol) was then added via syringeand the reaction mixture was stirred at 110° C. for 6 hours. The productwas isolated by silica gel chromatography (gradient from 40-100% ethylacetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%,acetonitrile in water with 0.1% TFA) to afford the title compound 21 asthe TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (s, 1H), 9.31 (s, 1H),8.33-8.24 (m, 2H), 7.82 (d, J=16.7 Hz, 1H), 7.77-7.66 (m, 3H), 7.58-7.50(m, 1H), 7.45-7.36 (m, 1H), 6.69 (d, J=16.7 Hz, 1H), 2.54 (s, 3H), 1.96(s, 6H). LCMS (m/z) 432.0 [M+H], Tr=3.56 min (LCMS method 1).

Example 22(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-nitroquinazolin-2-yl)amino)nicotinonitrile—Compound22

Step 1: Synthesis of 2-amino-3-bromo-5-nitrobenzoic Acid (Compound 22a)

A mixture of 2-amino-5-nitrobenzoic acid (5 g, 27 mmol, Sigma-Aldrich)and N-bromosuccinimide (6 g, 34 mmol) in N,N-dimethylformamide (100 mL)was stirred at room temperature for 14 hours. The reaction mixture waspoured into water (500 mL) and the solid product was filtered off andwashed with water to afford the title compound 22a. LCMS (m/z) 261.03[M+H], Tr=3.70 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-nitroquinazoline-2,4(1H,3H)-dione(Compound 22b)

A mixture of compound 22a (5 g, 22 mmol) and urea (20 g, 333 mmol) washeated at 200° C. for 3 hours. The reaction mixture was cooled down, anddiluted with water (100 mL). The solid product was filtered off andwashed with methanol (50 mL) and water (50 mL) to afford the titlecompound 22b. LCMS (m/z) 286.2 [M+H], Tr=3.21 min (LCMS method 1).

Step 3: Synthesis of 8-bromo-2-chloro-6-nitroquinazolin-4-amine(Compound 22c)

A mixture of compound 22b (5 g, 17 mmol), phosphorus(V) oxychloride (15mL) and N,N-dimethylformamide (4 drops) was heated at 120° C. for 14hours. The reaction mixture was cooled down, poured into ice watermixture (200 mL) and the solid product was filtered off. The solid wasdried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room temperature for 14 hours. Thereaction mixture was concentrated down under reduced pressure and waterwas added. The solid product was filtered off to afford the titlecompound 22c. ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (d, J=2.4 Hz, 1H), 8.79(d, J=2.4 Hz, 1H). LCMS (m/z) 303.0 [M+H], Tr=3.97 min (LCMS method 1).

Step 4: Synthesis of(E)-3-(4-(4-amino-2-chloro-6-nitroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 22d)

A mixture of compound 22c (152 mg, 0.5 mmol), compound 1c (170 mg, 0.6mmol), potassium phosphate tribasic monohydrate (230 mg, 1 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (33 mg, 0.05 mmol) was dissolved in a mixture ofN,N-dimethylformamide and water (10:1, 5.5 mL) under argon and thisreaction mixture was stirred at 80° C. for 7 hours. The product wasisolated by silica gel chromatography (gradient from 40-100% ethylacetate in iso-hexanes) to afford the title compound 22d. LCMS (m/z)379.9 [M+H], Tr=4.40 min (LCMS method 1).

Step 5: Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-nitroquinazolin-2-yl)amino)nicotinonitrile(Compound 22)

A mixture of compound 22d (110 mg, 0.29 mmol), 6-aminonicotinonitrile(171 mg, 1.45 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (13mg, 0.06 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (34 mg, 0.06mmol) was dissolved in N-methyl-2-pyrrolidone (5 mL) under argon.N,N-Diisopropylethylamine (514 μL, 2.95 mmol) was then added via syringeand the reaction mixture was stirred at 100° C. for 1 hour. The productwas isolated by silica gel chromatography (gradient from 40-100% ethylacetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%,acetonitrile in water with 0.1% TFA) to afford the title compound 22 asthe TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 9.43 (bs, 2H), 7.80 (d, J=16.7Hz, 1H), 7.77-7.50 (m, 7H), 7.48 (bs, 1H), 6.53 (d, J=16.7 Hz, 1H), 1.97(s, 6H). LCMS (m/z) 463.0 [M+H], Tr=3.98 min (LCMS method 1).

Example 23(E)-6-((4,6-Diamino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile—Compound23

Synthesis of(E)-6-((4,6-diamino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile(Compound 23)

Compound 22 (20 mg, 0.043 mmol) was dissolved in the methanol-aceticacid mixture (10:1, 2 mL), iron dust (20 mg, 0.358 mmol) was added inone portion and the reaction mixture was stirred at room temperature for24 hours. The product was isolated by silica gel chromatography(gradient from 10-30% methanol in ethyl acetate) and then repurified byreverse phase flash chromatography (5.5 g C-18 RediSep prepacked column,gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford thetitle compound 23 as the TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 9.22 (s,1H), 9.04 (s, 1H), 8.26-8.21 (m, 1H), 7.82 (d, J=16.6 Hz, 1H), 7.83-7.74(m, 1H), 7.68 (s, 2H), 7.51 (s, 1H), 7.38-7.32 (m, 1H), 7.11 (s, 1H),6.69 (d, J=16.6 Hz, 1H), 1.98 (s, 6H). LCMS (m/z) 433.1 [M+H], Tr=3.68min (LCMS method 1).

Example 24(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methoxyquinazolin-2-yl)amino)nicotinonitrile—Compound24

Step 1: Synthesis of 2-amino-3-bromo-5-methoxybenzoic Acid (Compound24a)

A mixture of 2-amino-5-methoxybenzoic acid (3.95 g, 23.6 mmol,Sigma-Aldrich) and N-bromosuccinimide (4.2 g, 23.6 mmol) inN,N-dimethylformamide (80 mL) was stirred at room temperature for 14hours. The reaction mixture was poured into water (400 mL) and the solidproduct was filtered off and washed with water to afford the titlecompound 24a. LCMS (m/z) 245.8 [M+H], Tr=4.06 min (LCMS method 1).

Step 2: Synthesis of 8-bromo-6-methoxyquinazoline-2,4(1H,3H)-dione(Compound 24b)

A mixture of compound 24a (2.19 g, 8.9 mmol) and urea (12 g, 200 mmol)was heated at 200° C. for 3 hours. The reaction mixture was cooled down,and diluted with water (100 mL). The solid product was filtered off andwashed with water (50 mL) to afford the title compound 24b.

Step 3: Synthesis of 8-bromo-2-chloro-6-methoxyquinazolin-4-amine(Compound 24c)

A mixture of compound 24b (2.45 g, 9 mmol), phosphorus(V) oxychloride(10 mL) and N,N-dimethylformamide (5 drops) was heated at 120° C. for 14hours. The reaction mixture was cooled down, poured into ice watermixture (200 mL) and the solid product was filtered off. The solid wasdried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room temperature for 14 hours. Thereaction mixture was concentrated down under reduced pressure and water(20 mL) was added. The solid product was filtered off to afford thetitle compound 24c. LCMS (m/z) 287.7 [M+H], Tr=4.33 min (LCMS method 1).

Step 4: Synthesis of(E)-3-(4-(4-amino-2-chloro-6-methoxyquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 24d)

A mixture of compound 24c (30 mg, 0.1 mmol), compound 1c (34 mg, 0.12mmol), potassium phosphate tribasic monohydrate (46 mg, 0.2 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (13 mg, 0.02 mmol) was dissolved in a mixture ofN,N-dimethylformamide and water (10:1, 2 mL) under argon and thisreaction mixture was stirred at 80° C. for 30 minutes. The product wasisolated by silica gel chromatography (gradient from 50-100% ethylacetate in iso-hexanes) to afford the title compound 24d. LCMS (m/z)364.9 [M+H], Tr=4.65 min (LCMS method 1).

Step 5: Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methoxyquinazolin-2-yl)amino)nicotinonitrile(Compound 24)

A mixture of compound 24d (15 mg, 0.041 mmol), 6-aminonicotinonitrile(24 mg, 0.21 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (4mg, 0.016 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (10 mg, 0.016mmol) was dissolved in N-methyl-2-pyrrolidone (1 mL) under argon.N,N-Diisopropylethylamine (37 μL, 0.21 mmol) was then added via syringeand the reaction mixture was stirred at 100° C. for 2 hours. The productwas isolated by silica gel chromatography (gradient from 60-100% ethylacetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%,acetonitrile in water with 0.1% TFA) to afford the title compound 24 asthe TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (bs, 1H), 11.99 (bs,1H), 9.46 (bs, 1H), 9.26 (bs, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.83 (d,J=16.7 Hz, 1H), 7.70 (s, 2H), 7.62-7.48 (m, 2H), 7.42-7.36 (m, 1H), 6.69(d, J=16.7 Hz, 1H), 3.95 (s, 3H), 1.98 (s, 6H). LCMS (m/z) 448.0 [M+H],Tr=3.95 min (LCMS method 1).

Example 25(E)-4-((4-Amino-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound25

Step 1: Synthesis of 2-amino-5-bromo-3-iodobenzoic Acid (Compound 25a)

A mixture of 2-amino-5-bromobenzoic acid (1 g, 4.6 mmol, Sigma-Aldrich)and N-iodosuccinimide (1.9 g, 8.4 mmol) in N,N-dimethylformamide (30 mL)was stirred at room temperature for 48 hours. The reaction mixture waspoured into water (100 mL). The solid product was filtered off andwashed with water to afford the title compound 25a. LCMS (m/z) 341.9[M+H], Tr=4.53 min (LCMS method 1).

Step 2: Synthesis of 6-bromo-8-iodoquinazoline-2,4(1H,3H)-dione(Compound 25b)

A mixture of compound 25a (1.2 g, 3.5 mmol) and urea (10 g, 166 mmol)was heated at 200° C. for 3 hours. The reaction mixture was cooled down,and diluted with water (100 mL). The solid product was filtered off andwashed with methanol (50 mL) and water (50 mL) to afford the titlecompound 25b.

Step 3: Synthesis of 6-bromo-2-chloro-8-iodoquinazolin-4-amine (Compound25c)

A mixture of compound 25b (5.33 g, 14.5 mmol), phosphorus(V) oxychloride(30 mL) and N,N-dimethylformamide (3 drops) was heated at 120° C. for 14hours. The reaction mixture was cooled down, poured into ice watermixture (200 mL) and the solid product was filtered off. The solid wasdried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room temperature for 14 hours. Thereaction mixture was concentrated down under reduced pressure andsubjected to silica gel column chromatography (gradient from 10-50%ethyl acetate in iso-hexanes) to afford the title compound 25c. ¹H NMR(400 MHz, DMSO-d₆) δ 7.97 (d, J=2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H),6.78 (bs, 2H). LCMS (m/z) 383.9 [M+H], Tr=5.98 min (LCMS method 1).

Step 4: Synthesis of(E)-3-(4-(4-amino-6-bromo-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 25d)

A mixture of compound 25c (120 mg, 0.31 mmol), compound 1c (106 mg, 0.37mmol), potassium phosphate tribasic monohydrate (143 mg, 0.62 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (40 mg, 0.062 mmol) was dissolved in a mixture ofN,N-dimethylformamide and water (10:1, 3 mL) under argon and thisreaction mixture was stirred at room temperature for 24 hours. Thereaction was quenched by addition of saturated ammonium chloride and theproduct was isolated by silica gel chromatography (gradient from 30-60%ethyl acetate in iso-hexanes) to afford the title compound 25d. LCMS(m/z) 412.8 [M+H], Tr=4.62 min (LCMS method 1).

Step 5: Synthesis of(E)-4-((4-amino-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 25)

A mixture of compound 25d (55 mg, 0.13 mmol) and 4-aminobenzonitrile (20mg, 0.17 mmol, Sigma-Aldrich) in isopropanol (2 mL) was heated undermicrowave conditions at 170° C. for 30 minutes. The reaction mixture wasconcentrated down under reduced pressure and purified by silica gelcolumn chromatography (gradient from 0-100% ethyl acetate iniso-hexanes) to afford the title compound 25. ¹H NMR (400 MHz, DMSO-d₆)δ 9.57 (s, 1H), 8.47 (d, J=2.2 Hz, 1H), 7.75 (d, J=16.7 Hz, 1H),7.68-7.63 (m, 3H), 7.52 (s, 2H), 7.32-7.21 (m, 2H), 6.56 (d, J=16.7 Hz,1H), 1.92 (s, 6H). LCMS (m/z) 495.1 [M+H], Tr=4.58 min (LCMS method 1).

Example 26(E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyrazine-2-carbonitrile—Compound26

Synthesis of(E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyrazine-2-carbonitrile(Compound 26)

Compound 20d (92 mg, 0.21 mmol), 5-aminopyrazine-2-carbonitrile (60 mg,0.50 mmol, Ark Pharm Inc, AK-21935), N,N-diisopropylethylamine (174 μL,1.0 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24mg, 0.042 mmol) and palladium (II) acetate (9 mg, 0.042 mmol) werecombined under argon in N-methyl-2-pyrrolidone (2 mL). The reaction washeated at 100° C. in a sealed vessel for 7 hours. The reaction mixturewas cooled down to room temperature, purified by silica gelchromatography (gradient from 50-100% ethyl acetate in iso-hexanes) andthen re-purified by reverse phase chromatography (5-100% acetonitrile inwater with 0.1% trifluoroacetic acid) to afford the TFA salt of compound26. ¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.20 (s, 1H), 7.74 (d,J=16.7 Hz, 1H), 7.77-7.60 (m, 2H), 7.57 (s, 2H), 6.56 (d, J=16.7 Hz,1H), 1.94 (s, 6H). LCMS (m/z) 436.9 [M+H], Tr=3.59 min (LCMS method 1).

Example 27(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyridazine-3-carbonitrile—Compound27

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyridazine-3-carbonitrile(compound 27)

Compound 20d (92 mg, 0.21 mmol), 6-aminopyridazine-3-carbonitrile (60mg, 0.50 mmol, Matrix Scientific, 112287), N,N-diisopropylethylamine(174 μL, 1.0 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (24 mg, 0.042mmol) and palladium (II) acetate (9 mg, 0.042 mmol) were combined underargon in N-methyl-2-pyrrolidone (2 mL). The reaction was heated at 100°C. in a sealed vessel for 7 hours. The reaction mixture was cooled downto room temperature, purified by silica gel chromatography (gradientfrom 50-100% ethyl acetate in iso-hexanes) and then re-purified byreverse phase chromatography (5-100% acetonitrile in water with 0.1%trifluoroacetic acid) to afford the TFA salt of compound 27. ¹H NMR (400MHz, DMSO-d₆) δ 8.18 (bs, 1H), 8.06 (bs, 1H), 7.73 (d, J=16.7 Hz, 1H),7.71-7.58 (m, 2H), 7.54 (s, 2H), 6.55 (d, J=16.7 Hz, 1H), 1.93 (s, 6H).LCMS (m/z) 436.9 [M+H], Tr=3.73 min (LCMS method 1).

Example 28(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)benzonitrile—Compound28

Step 1: Synthesis of 8-bromo-5-methoxyquinazoline-2,4(1H,3H)-dione(Compound 28a)

A mixture of 2-amino-3-bromo-6-methoxybenzoic acid (2 g, 8.1 mmol, ArkPharm Inc, AK137474) and urea (12 g, 200 mmol) was heated at 200° C. for2 hours. The reaction mixture was cooled down, and diluted with water(100 mL). The solid product was filtered off and washed with water (50mL) to afford the title compound 28a.

Step 2: Synthesis 8-bromo-2-chloro-5-methoxyquinazolin-4-amine (Compound28b)

A mixture of compound 28a (4.67 g, 17 mmol), phosphorus(V) oxychloride(20 mL) and N,N-dimethylformamide (3 drops) was heated at 120° C. for 14hours. The reaction mixture was cooled down, poured into ice watermixture (200 mL) and the solid product was filtered off. The solid wasdried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room temperature for 14 hours. Thereaction mixture was concentrated down under reduced pressure and thesolid residue was subjected to extraction with acetone. The acetonesolution was concentrated down under reduced pressure to afford thetitle compound 28b. ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.26 (s,1H), 8.02 (d, J=8.7 Hz, 1H), 6.95 (d, J=8.7 Hz, 1H), 3.98 (s, 3H). LCMS(m/z) 288.1 [M+H], Tr=3.74 min (LCMS method 1).

Step 3: Synthesis of(E)-3-(4-(4-amino-2-chloro-5-methoxyquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 28c)

A mixture of compound 28b (100 mg, 0.35 mmol), compound 1c (118 mg, 0.42mmol), potassium phosphate tribasic monohydrate (159 mg, 0.69 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (23 mg, 0.035 mmol) was dissolved in a mixture ofN,N-dimethylformamide and water (10:1, 5 mL) under argon and thisreaction mixture was stirred at 80° C. for 30 minutes. The product wasisolated by silica gel chromatography (gradient from 60-100% ethylacetate in iso-hexanes) to afford the title compound 28c. LCMS (m/z)364.9 [M+H], Tr=4.38 min (LCMS method 1).

Step 4: Synthesis of(E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)benzonitrile(Compound 28)

A mixture of compound 28c (37 mg, 0.1 mmol), 4-aminobenzonitrile (60 mg,0.5 mmol, Sigma-Aldrich), palladium(II) acetate (4 mg, 0.02 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (12 mg, 0.02mmol) was dissolved in N-methyl-2-pyrrolidone (2 mL) under argon.N,N-Diisopropylethylamine (87 μL, 0.5 mmol) was then added via syringeand the reaction mixture was stirred at 110° C. for 6 hours. The productwas isolated by silica gel chromatography (gradient from 50-100% ethylacetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%,acetonitrile in water with 0.1% TFA) to afford the title compound 28 asthe TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ 7.90-7.65 (m, 3H), 7.71 (d,J=16.7 Hz, 1H), 7.58-7.45 (m, 4H), 7.07 (s, 1H), 6.55 (d, J=16.7 Hz,1H), 4.07 (s, 3H), 1.95 (s, 6H). LCMS (m/z) 447.0 [M+H], Tr=3.85 min(LCMS method 1).

Example 29(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)nicotinonitrile—Compound29

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)nicotinonitrile(Compound 29)

Compound 28c (37 mg, 0.1 mmol), 6-aminonicotinonitrile (60 mg, 0.5 mmol,Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (87 μL, 0.5 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (12 mg, 0.02mmol) and palladium (II) acetate (4 mg, 0.02 mmol) were combined underargon in N-methyl-2-pyrrolidone (2 mL). The reaction was heated at 110°C. in a sealed vessel for 6 hours. The reaction mixture was cooled downto room temperature, purified by silica gel chromatography (gradientfrom 50-100% ethyl acetate in iso-hexanes) and then re-purified byreverse phase chromatography (5-100% acetonitrile in water with 0.1%trifluoroacetic acid) to afford the TFA salt of compound 29. ¹H NMR (400MHz, DMSO-d₆) δ 13.31 (bs, 1H), 11.92 (bs, 1H), 9.49 (s, 1H), 9.09 (s,1H), 8.27 (d, J=8.4 Hz, 1H), 7.82 (d, J=16.7 Hz, 1H), 7.77 (d, J=9.2 Hz,1H), 7.68 (s, 2H), 7.55-7.40 (m, 2H), 7.30 (d, J=8.4 Hz, 1H), 6.69 (d,J=16.7 Hz, 1H), 4.13 (s, 3H), 1.97 (s, 6H). LCMS (m/z) 448.0 [M+H],Tr=3.60 min (LCMS method 1).

Example 30(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)benzonitrile—Compound30

Step 1: Synthesis of 8-bromo-2-chloro-N-methylquinazolin-4-amine(Compound 30a)

8-Bromo-2,4-dichloroquinazoline (556 mg, 2 mmol, Ark Pharm Inc.,AK-28703) was dissolved in 6 mL of 20% solution of methylamine inethanol and the reaction was stirred at room temperature for 15 minutes.Volatiles were removed under reduced pressure and the solid residue wassuspended in water. The solid product was filtered off and washed withwater (3×5 mL) and pentane (3×5 mL) to give the title compound 30a. ¹HNMR (400 MHz, DMSO-d₆) δ 8.96 (d, J=4.7 Hz, 1H), 8.19 (dd, J=8.3 Hz,J=1.2 Hz, 1H), 8.11 (dd, J=7.7 Hz, J=1.2 Hz, 1H), 7.42 (t, J=7.9 Hz,1H), 3.00 (d, J=4.3 Hz, 3H). HRMS: (ESI+) calculated for C₉H₈N₃BrCl[M+H] 271.9585, found 271.9585. LCMS (m/z) 272.0 [M+H], Tr 3.80 min(LCMS method 1).

Step 2: Synthesis of(E)-3-(4-(2-chloro-4-(methylamino)quinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 30b)

A mixture of compound 30a (110 mg, 0.4 mmol), compound 1c (147 mg, 0.52mmol), potassium phosphate tribasic monohydrate (138 mg, 0.6 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (26 mg, 0.04 mmol) was dissolved in a mixture ofN,N-dimethylformamide and water (85:15, 5 mL) under argon and thisreaction mixture was stirred at 80° C. for 20 minutes. The reactionmixture was concentrated down under reduced pressure and the product wasisolated by silica gel chromatography (gradient from 50-80% ethylacetate in iso-hexanes) to afford the title compound 30b. ¹H NMR (400MHz, DMSO-d₆) δ 8.88 (d, J=4.4 Hz, 1H), 8.25 (dd, J=8.2 Hz, J=1.5 Hz,1H), 7.67-7.58 (m, 2H), 7.53 (dd, J=7.2 Hz, J=1.5 Hz, 1H), 7.43 (s, 2H),6.46 (d, J=16.7 Hz, 1H), 3.01 (d, J=4.4 Hz, 3H), 1.85 (s, 6H). HRMS:(ESI+) calculated for C₂₀H₁₅N₄Cl [M+H] 349.1215, found 349.1216. LCMS(m/z) 349.1 [M+H], Tr 4.51 min (LCMS method 1).

Step 3: Synthesis of(E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)benzonitrile(compound 30)

A mixture of compound 30b (52 mg, 0.15 mmol), 4-aminobenzonitrile (90mg, 0.75 mmol, Sigma-Aldrich), palladium(II) acetate (20 mg, 0.064 mmol)and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg,0.064 mmol) was dissolved in N-methyl-2-pyrrolidone (3 mL) under argon.N,N-Diisopropylethylamine (150 μL, 0.85 mmol) was then added via syringeand the reaction mixture was stirred at 110° C. for 3 hours. Thereaction mixture was concentrated down under reduced pressure and theproduct was isolated by silica gel chromatography (gradient from 80-100%ethyl acetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%,acetonitrile in water) to afford the title compound 30. ¹H NMR (400 MHz,DMSO-d₆) δ 9.54 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H),7.77-7.70 (m, 3H), 7.51 (s, 2H), 7.46 (d, J=7.5 Hz, 1H), 7.35 (t, J=7.7Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 6.54 (d, J=16.7 Hz, 1H), 3.06 (d, J=4.3Hz, 3H), 1.90 (s, 6H). HRMS: (ESI+) calculated for C₂₇H₂₃N₆ [M+H]431.1979, found 431.1977. LCMS (m/z) 431.2 [M+H], Tr 3.67 min (LCMSmethod 1).

Example 31(E)-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)nicotinonitrile—Compound31

Synthesis of(E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)nicotinonitrile(Compound 31)

A mixture of compound 30b (52 mg, 0.15 mmol), 6-aminonicotinonitrile (90mg, 0.75 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (20 mg,0.064 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.064mmol) was dissolved in N-methyl-2-pyrrolidone (3 mL) under argon.N,N-Diisopropylethylamine (150 μL, 0.85 mmol) was then added via syringeand the reaction mixture was stirred at 110° C. for 4 hours. Thereaction mixture was concentrated down under reduced pressure and theproduct was isolated by silica gel chromatography (gradient from 80-100%ethyl acetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%,acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFAsalt of the title compound 31. ¹H NMR (400 MHz, DMSO-d₆) δ 13.53 (s,1H), 12.28 (s, 1H), 10.13 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.29 (d,J=8.8 Hz, 1H), 7.88-7.80 (m, 2H), 7.80-7.72 (m, 1H), 7.71 (s, 2H),7.59-7.49 (m, 1H), 7.46-7.41 (m, 1H), 6.70 (d, J=16.7 Hz, 1H), 3.21 (d,J=4.4 Hz, 3H), 1.96 (s, 6H). HRMS: (ESI+) calculated for C₂₆H₂₂N₇ [M+H]432.1931, found 432.1929. LCMS (m/z) 432.2 [M+H], Tr 3.53 min (LCMSmethod 1).

Example 32(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile—Compound32

Step 1: Synthesis of4-((4-amino-8-(trimethylstannyl)quinazolin-2-yl)amino)benzonitrile(Compound 32a)

To a mixture of 8a (1000 mg, 2.94 mmol) andtetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) in drydioxane (5 mL) was added hexamethylditin (1 mL, 4.82 mmol) under argon.The reaction mixture was heated to 100° C. for 14 hours under argon,then cooled down to room temperature and directly purified by silica gelchromatography (gradient from 25-50% ethyl acetate in iso-hexanes) toafford the title compound 32a. ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H),8.08-8.18 (m, 3H), 7.73 (d, J=9.9 Hz, 1H), 7.64 (d, J=8.9 Hz, 2H), 7.51(bs, 2H), 7.20-7.28 (m, 1H), 0.36 (s, 9H). LCMS (m/z) 424.0 [M−H],Tr=4.84 min (LCMS method 1).

Step 2: Synthesis of (E)-3-(4-bromo-3,5-dimethoxyphenyl)acrylonitrile(Compound 32b)

To a solution of 4-bromo-3,5-dimethoxybenzaldehyde (24.5 g, 100 mmol,Ark Pharm Inc., AK-34641) and diethylcyanomethyl phosphonate (18.6 g,105 mmol) in anhydrous 2-methyltetrahydrofuran (400 mL) was slowly addedpotassium t-butoxide (12.3 g, 110 mmol) at 0° C. under argon. Thereaction mixture was vigorously stirred at 0° C. for 1 hour and then atroom temperature for 3 hours. The reaction mixture was diluted withethyl acetate and washed twice with water and once with brine. Theorganic layer was dried over MgSO₄ and, filtered through a 3 cm layer ofsilica gel which was washed with additional ethyl acetate. The combinedorganics were concentrated down under reduced pressure and the solidresidue was treated in sonic bath with hexane/diethyl ether mixture(1/3) for 3 minutes. The solid product was filtered off and washed withhexane to afford the title compound 32b. ¹H NMR (400 MHz, DMSO-d₆) δ7.61 (d, J=16.7 Hz, 1H), 7.06 (s, 2H), 6.65 (d, J=16.7 Hz, 1H), 3.87 (s,6H). LCMS (m/z) no MS signal, Tr 2.50 min (LCMS method 2).

Step 3: Synthesis of(E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 32)

A mixture of compound 32a (20 mg, 0.047 mmol), compound 32b (20 mg,0.075 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C.for 2 hours. The reaction mixture was concentrated down under reducedpressure, purified by silica gel chromatography (gradient from 50-100%ethyl acetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%,acetonitrile in water with 0.1% TFA) to afford the TFA salt of the titlecompound 32. ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (bs, 1H), 9.72-9.53 (m,2H), 7.88-7.83 (m, 2H), 7.77 (d, J=16.7 Hz, 1H), 7.71 (d, J=7.8 Hz, 2H),7.58 (bs, 1H), 7.54 (bs, 1H), 7.41-7.34 (m, 1H), 7.16 (s, 2H), 6.76 (d,J=16.7 Hz, 1H), 3.72 (s, 6H). LCMS (m/z) 449.0 [M+H], Tr=3.48 min (LCMSmethod 1).

Example 33(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile—Compound33

Step 1: Synthesis of4-((8-(trimethylstannyl)quinazolin-2-yl)amino)benzonitrile (Compound33a)

To a mixture of 1a (1000 mg, 3.07 mmol) andtetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) in drydioxane (5 mL) was added hexamethylditin (1 mL, 4.82 mmol) under argon.The reaction mixture was heated to 110° C. for 4 hours under argon, thencooled down to room temperature and directly purified by silica gelchromatography (gradient from 0-30% ethyl acetate in iso-hexanes) toafford the title compound 33a. ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s,1H), 9.47 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.31-8.24 (m, 2H), 8.09-8.02(m, 1H), 7.90-7.85 (m, 2H), 7.60-7.51 (m, 1H), 0.05 (s, 9H). LCMS (m/z)409.0 [M+H], Tr=5.54 min (LCMS method 1).

Step 2: Synthesis of(E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 33)

A mixture of compound 33a (20 mg, 0.048 mmol), compound 32b (20 mg,0.075 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C.for 2 hours. The reaction mixture was concentrated down under reducedpressure, purified by silica gel chromatography (gradient from 0-50%ethyl acetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%,acetonitrile in water with 0.1% TFA) to afford the TFA salt of the titlecompound 33. ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 9.40 (s, 1H),7.96 (dd, J=8.1, 1.4 Hz, 1H), 7.78-7.85 (m, 3H), 7.71 (dd, J=7.2, 1.4Hz, 1H), 7.44-7.54 (m, 3H), 7.21 (s, 2H), 6.77 (d, J=16.7 Hz, 1H), 3.62(s, 6H). LCMS (m/z) 433.98 [M+H], Tr=4.39 min (LCMS method 1).

Example 34(E)-6-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)nicotinonitrile—Compound34

Step 1: Synthesis of 8-bromo-2-chloroquinazolin-4(3H)-one (Compound 34a)

Aqueous sodium hydroxide (30 mL, 0.2 M, 6 mmol) was added into asolution of 8-bromo-2,4-dichloroquinazoline (556 mg, 2 mmol, Ark PharmInc., AK-28703) in tetrahydrofuran (30 mL). The reaction mixture wasstirred at room temperature for 0.5 hour. Then the reaction mixture wasacidified with glacial acetic acid to pH=5 and concentrated down underreduced pressure. Water was added and the solid product was filtered offand washed with water (3×20 ml) to afford the title compound 34a. ¹H NMR(400 MHz, DMSO-d₆) δ 13.51 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.09 (d,J=7.8 Hz, 1H), 7.42-7.51 (m, 1H). HRMS: (ESI+) calculated forC₈H₄ON₂BrClNa [M+Na] 280.9088, found 280.9089. LCMS (m/z) 259.0 [M+H],Tr 3.58 min (LCMS method 1).

Step 2: Synthesis of(E)-3-(4-(2-chloro-4-oxo-3,4-dihydroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile(Compound 34b)

A mixture of compound 34a (74 mg, 0.28 mmol), compound 1c (120 mg, 0.42mmol), potassium phosphate tribasic monohydrate (200 mg, 0.87 mmol) and[1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complexwith dichloromethane (30 mg, 0.05 mmol) was dissolved in a mixture ofN,N-dimethylformamide and water (10:1, 3.3 mL) under argon and thismixture was stirred at 80° C. for 2 hours. The product was isolated bysilica gel chromatography (gradient from 0-100% ethyl acetate iniso-hexanes) to afford the title compound 34b. ¹H NMR (400 MHz, DMSO-d₆)δ 13.30 (bs, 1H), 8.16 (dd, J=7.7, 1.8 Hz, 1H), 7.67-7.51 (m, 3H), 7.43(s, 2H), 6.46 (d, J=16.7 Hz, 1H), 1.88 (s, 6H). LCMS (m/z) 336.1 [M+H],Tr=4.24 (LCMS method 1).

Step 3: Synthesis of(E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)nicotinonitrile(Compound 34)

A mixture of compound 34b (80 mg, 0.24 mmol), 6-aminonicotinonitrile(200 mg, 1.68 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (20mg, 0.09 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (100 mg, 0.17mmol) was dissolved in N-methyl-2-pyrrolidone (3 mL) under argon.N,N-Diisopropylethylamine (1 mL, 5.7 mmol) was then added via syringeand the reaction mixture was stirred at 100° C. for 1 hour. The productwas isolated by silica gel flash chromatography (gradient from 0-100%ethyl acetate in iso-hexanes) and then repurified by reverse phase flashchromatography (5.5 g C-18 RediSep pre-packed column, gradient 0-100%acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFAsalt of compound 34. ¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (bs, 1H), 10.26(bs, 1H), 8.74 (bs, 1H), 8.10 (dd, J=7.8, 1.6 Hz, 1H), 7.94-7.81 (m,1H), 7.69 (d, J=16.7 Hz, 1H), 7.59-7.36 (m, 5H), 6.51 (d, J=16.7 Hz,1H), 1.94 (s, 6H). LCMS (m/z) 418.9 [M+H], Tr=4.11 min (LCMS method 1).

Example 35(E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound35

Step 1: Synthesis of (E)-3-(4-bromo-3,5-diethylphenyl)acrylonitrile(Compound 35a)

To a solution of 2,5-dibromo-1,3-diethylbenzene (2920 mg, 10 mmol,Oakwood Products, Inc.—034265) in anhydrous acetonitrile (25 mL) wasadded palladium(II) acetate (224 mg, 1 mmol), acrylonitrile (1060 mg, 20mmol), tri(o-tolyl)phosphine (913 mg, 3 mmol) and triethylamine (4 mL,30 mmol) then the mixture was purged with argon and heated at 70° C. for3 hours. The reaction mixture was filtered through Celite and the filterpad was washed with tetrahydrofuran (10 mL). The filtrate was evaporatedthen re-dissolved with ethyl acetate (50 mL). The solution was washedwith water (50 mL). The water layer was back extracted with ethylacetate (50 mL). The combined organics were washed with brine (30 mL),dried over sodium sulfate, filtered and concentrated under reducedpressure to give a crude residue. This was subjected to silica gelchromatography (gradient from 0-20% ethyl acetate in iso-hexanes) toafford the title compound 35a. ¹H NMR (400 MHz, CDCl₃) δ 7.31 (d, J=16.6Hz, 1H), 7.12 (s, 2H), 5.86 (d, J=16.6 Hz, 1H), 2.79 (q, J=7.5 Hz, 4H),1.22 (t, J=7.5 Hz, 6H). LCMS (m/z) no MS signal, Tr=3.07 min (LCMSmethod 2).

Step 2: Synthesis of(E)-3-(3,5-diethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylonitrile(Compound 35b)

A mixture of compound 35a (300 mg, 1.14 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (432 mg,1.70 mmol), potassium carbonate (471 mg, 3.4 mmol), palladium(II)acetate (13 mg, 0.06 mmol) anddicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (SPhos, 58mg, 0.14 mmol) in dry N,N-dimethylformamide (20 mL) was purged withargon and heated at 100° C. for 2 hour. The reaction mixture wasfiltered through Celite and the filter pad was washed withtetrahydrofuran (10 mL). The filtrate was evaporated then re-dissolvedwith ethyl acetate (50 mL). The solution was washed with water (50 mL).The water layer was back extracted with ethyl acetate (50 mL). Thecombined organics were washed with brine (30 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure to give acrude residue which was purified by silica gel chromatography (gradientfrom 0-15% ethyl acetate in iso-hexanes) to afford compound 35b. ¹H NMR(400 MHz, CDCl₃) δ 7.33 (d, J=16.6 Hz, 1H), 7.04 (s, 2H), 5.85 (d,J=16.6 Hz, 1H), 2.67 (q, J=7.6 Hz, 4H), 1.38 (s, 12H), 1.20 (t, J=7.6Hz, 6H). LCMS (m/z) no MS signal, Tr=3.07 min (LCMS method 2).

Step 3: Synthesis of(E)-3-(4-(4-amino-2-chloroquinazolin-8-yl)-3,5-diethylphenyl)acrylonitrile(Compound 35c)

A mixture of 8-bromo-2-chloroquinazolin-4-amine (90 mg, 0.35 mmol, ArkPharm Inc, AK-28702), compound 35b (130 mg, 0.42 mmol), potassiumphosphate tribasic (96 mg, 0.45 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (23 mg,0.04 mmol) was dissolved in N,N-dimethylformamide:water mixture (80:20,5 mL) under argon. The reaction was heated at 80° C. for 60 minutes. Thereaction mixture was cooled down to room temperature and diluted withwater and ethyl acetate. The organic layer was separated and washedtwice with brine, dried over magnesium sulfate, 1 volume equivalent ofhexane added and this mixture was filtered through a 2 cm layer ofsilica gel which was washed with additional ethyl acetate. Combinedorganics were concentrated down under reduced pressure and the residuewas treated with hexane in a sonic bath. The solid product was filteredoff and washed twice with hexane to afford the title compound 35c. ¹HNMR (400 MHz, DMSO-d₆) δ 8.39 (bs, 2H), 8.29 (dd, J=7.2, 2.5 Hz, 1H),7.67 (d, J=16.7 Hz, 1H), 7.61-7.54 (m, 2H), 7.46 (s, 2H), 6.52 (d,J=16.7 Hz, 1H), 2.22-2.01 (m, 4H), 0.91 (t, J=7.5 Hz, 6H). LCMS (m/z)363.3 [M+H], Tr=2.68 min (LCMS method 2).

Step 4: Synthesis of(E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 35)

A mixture of compound 35c (40 mg, 0.11 mmol), 4-cyanoaniline (18 mg,0.154 mmol, Sigma-Aldrich) and hydrogen chloride solution in 1,4-dioxane(4M, 3 μL, 0.011 mmol) in dry N-methyl-2-pyrrolidone (1 mL) was heatedunder argon at 120° C. for 12 hours. The reaction mixture was cooleddown to room temperature and purified directly by HPLC reverse phasechromatography (gradient 0-100% acetonitrile in water with 0.1%trifluoroacetic acid) to afford the TFA salt of compound 35. ¹H NMR (400MHz, DMSO-d₆) δ 10.57-9.84 (m, 1H), 9.82-8.84 (m, 2H), 8.27 (bs, 1H),7.86-7.22 (m, 7H), 6.62 (d, J=16.8 Hz, 1H), 2.40-1.98 (m, 4H), 0.94 (t,J=7.2 Hz, 6H). LCMS (m/z) 445.4 [M+H], Tr=2.59 min (LCMS method 2).

Example 36(E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)nicotinonitrile—Compound36

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)nicotinonitrile(Compound 36)

Compound 35c (40 mg, 0.11 mmol), 6-aminonicotinonitrile (53 mg, 0.44mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (28 mg, 0.22mmol) and[(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (9 mg, 0.011 mmol) were combined under argon inN-methyl-2-pyrrolidone (1 mL). The reaction was heated at 120° C. in asealed vessel for 4 hours. The reaction mixture was cooled down to roomtemperature and purified directly by HPLC reverse phase chromatography(gradient 0-100% acetonitrile in water with 0.1% trifluoroacetic acid)to afford the TFA salt of compound 36. ¹H NMR (400 MHz, DMSO-d₆) δ 13.54(bs, 1H), 12.09 (bs, 1H), 9.62 (bs, 1H), 9.38 (bs, 1H), 8.46 (d, J=8.2Hz, 1H), 8.37-8.15 (m, 1H), 7.94-7.83 (m, 2H), 7.80-7.66 (m, 3H),7.56-7.27 (m, 2H), 6.76 (d, J=16.7 Hz, 1H), 2.40-2.01 (m, 4H), 0.94 (t,J=7.5 Hz, 6H). LCMS (m/z) 446.4 [M+H], Tr=1.98 min (LCMS method 2).

Example 37(E)-1-(2-((4-Cyanophenyl)amino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-4-yl)urea—Compound37

Synthesis of(E)-1-(2-((4-cyanophenyl)amino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-4-yl)urea(Compound 37)

Compound 2 (42 mg, 0.10 mmol) was suspended in dry dichloromethane (2mL), and N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) was added to thesuspension followed by dropwise addition of phosgene (0.5 mL, 20%solution in toluene). The mixture was stirred at 50° C. for 1 hour.Another portion of N,N-diisopropylethylamine (0.1 mL, 0.57 mmol) andphosgene (0.2 mL, 20% solution in toluene) was added to the reactionmixture and this mixture was stirred at 50° C. for another 1 hour. Themixture was cooled down to room temperature and saturated aqueousammonia (1 mL) was added. Volatiles were removed under reduced pressureand the crude residue was purified by HPLC using gradient from 50-100%acetonitrile in water (HPLC preparative column Phenomenex Gemini 10u,C18, 250×21.2 mm, 10 mL/min) to afford the title compound 37. ¹H NMR(400 MHz, DMSO-d₆) δ 9.35 (bs, 1H), 8.26-8.07 (m, 1H), 7.78-7.65 (m,3H), 7.62-7.45 (m, 3H), 7.44-7.30 (m, 3H), 7.29-7.16 (m, 3H), 6.43 (d,J=16.7 Hz, 1H), 1.81 (s, 6H). LCMS (m/z) 460.3 [M+H], Tr=3.98 min (LCMSmethod 1).

Example 38(E)-4-((4-Amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound38

Step 1: Synthesis of 4-bromo-3,5-dimethylbenzoic Acid (Compound 38a)

4-Bromo-3,5-dimethylbenzonitrile (630 mg, 3 mmol, Ark Pharm Inc,AK-44760) was dissolved in ethanol (1 mL), and 8M sodium hydroxidesolution (5 mL) was added and this reaction mixture was stirred in asealed vessel at 120° C. for 12 hours. The reaction mixture was dilutedwith water (100 mL) and washed with diethylether (2×50 mL), aqueouslayer was acidified with concentrated hydrochloric acid (to pH=3) andextracted with diethylether (2×100 mL). Combined organic layers weredried over sodium sulfate and concentrated down under reduced pressureto afford the title compound 38a. ¹H NMR (600 MHz, DMSO-d₆) δ 7.72 (s,2H), 2.41 (s, 6H).

Step 2: Synthesis of 1-(4-bromo-3,5-dimethylphenyl)ethanone (Compound38b)

Compound 38a (100 mg, 0.44 mmol) was suspended in dry 1,4-dioxane (5 mL)and methyllithium (0.8 mL, 1.6 M solution in diethyl ether) was addeddropwise under argon. The mixture was stirred at room temperature for 1hour. The reaction was quenched by addition of methanol (10 mL) andconcentrated down under reduced pressure. The solid residue wasextracted with ethyl acetate (3×10 mL). Combined organic solutions wereconcentrated down under reduced pressure to afford the title compound38b. LCMS (m/z) 227.0 [M+H], Tr=4.65 min (LCMS method 1).

Step 3: Synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)but-2-enenitrileand (Z)-3-(4-bromo-3,5-dimethylphenyl)but-2-enenitrile (Compound 38c andCompound 38d)

Compound 38b (95 mg, 0.42 mmol) and diethyl (cyanomethyl)phosphonate (70μL, 0.40 mmol) were dissolved in dry dichloromethane (5 mL). Cesiumcarbonate (1 g, 3.07 mmol) was added and the solution was slowlyconcentrated down under reduced pressure at 30° C. The resulting solidwas allowed to stand at room temperature for 4 hours. Dichloromethanewas added to the residue and the solids were filtered off. The solventwas removed under reduced pressure and the crude product was purified bysilica gel chromatography using gradient from 0-10% ethyl acetate iniso-hexanes to afford the title compound 38c LCMS (m/z) 250.0 [M+H],Tr=5.01 min (LCMS method 1); and the title compound 38d LCMS (m/z) 250.0[M+H], Tr=4.48 min (LCMS method 1).

Step 4: Synthesis of(E)-4-((4-amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 38)

A mixture of compound 32a (20 mg, 0.047 mmol), compound 38c (20 mg,0.080 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C.for 14 hours. The reaction mixture was concentrated down under reducedpressure, purified by silica gel chromatography (gradient from 50-100%ethyl acetate in iso-hexanes) and then re-purified on HPLC (preparativecolumn Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10 mL/min, gradientfrom 10-100% acetonitrile in water) to afford the title compound 38. ¹HNMR (600 MHz, DMSO-d₆) δ 8.23 (bs, 1H), 7.83-7.72 (m, 2H), 7.60-7.29 (m,7H), 6.17 (q, J=1.0 Hz, 1H), 2.52-2.51 (m, 3H), 1.96 (s, 6H). LCMS (m/z)430.9 [M+H], Tr=3.83 min (LCMS method 1).

Example 39(Z)-4-((4-Amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound39

Synthesis of(Z)-4-((4-amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile(Compound 39)

A mixture of compound 32a (20 mg, 0.047 mmol), compound 38d (18 mg,0.072 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C.for 14 hours. The reaction mixture was concentrated down under reducedpressure, purified by silica gel chromatography (gradient from 50-100%ethyl acetate in iso-hexanes) and then re-purified on HPLC (preparativecolumn Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10 mL/min, gradientfrom 10-100% acetonitrile in water) to afford the title compound 38. ¹HNMR (600 MHz, DMSO-d₆) δ 8.22 (bs, 1H), 7.84-7.71 (m, 4H), 7.62-7.29 (m,5H), 5.89-5.79 (m, 1H), 2.36 (d, J=1.5 Hz, 3H), 1.97 (s, 6H). LCMS (m/z)430.9 [M+H], Tr=3.76 min (LCMS method 1).

Example 404-((4-Amino-8-(4-(2-cyanoprop-1-en-1-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile—Compound40 (Mixture E/Z=1/1)

Step 1: Synthesis of 4-bromo-3,5-dimethylbenzaldehyde (Compound 40a)

A mixture of 4-bromo-3,5-dimethylbenzonitrile (2 g, 9.57 mmol, Ark PharmInc, AK-44760) in dichloromethane (25 mL) was cooled to −62° C. Asolution of diisobutylaluminium hydride (1M in dichloromethane, 11 mL)was added dropwise and the reaction was left to reach room temperatureduring 2 hours. After that, 5% aqueous solution of hydrochloric acid (10mL) was added and the reaction mixture was heated to reflux for 30minutes. Then, the reaction mixture was diluted with dichloromethane,washed with brine. The organic layer was dried over calcium chloride.The solvent was removed under reduced pressure and the crude product wassubjected to silica gel chromatography (gradient from 0-10% ethylacetate in iso-hexanes) to afford the title compound 40a. ¹H NMR (400MHz, CDCl₃) δ 9.93 (s, 1H), 7.57 (s, 2H), 2.50 (s, 6H). HRMS: (TOF CI+)calculated for C₉H₁₀BrO [M+H] 212.9915, found 212.9913. LCMS (m/z) 213.0[M+H], Tr=4.59 min (LCMS method 1).

Step 2: Synthesis of3-(4-bromo-3,5-dimethylphenyl)-2-methylacrylonitrile (Compound 40b)Mixture E/Z=1/1

Compound 40a (100 mg, 0.47 mmol) and diethyl (1-cyanoethyl)phosphonate(70 μL, 0.40 mmol) were dissolved in dry dichloromethane (5 mL). Cesiumcarbonate (1 g, 3.07 mmol) was added and the solution was slowlyconcentrated down under reduced pressure at 30° C. The resulting solidwas allowed to stand at room temperature for 4 hours. Dichloromethanewas added to the residue and the solids were filtered off. The solventwas removed under reduced pressure and the crude product was purified bysilica gel chromatography using gradient from 0-10% ethyl acetate iniso-hexanes to afford the title compound 40b as a 1:1 mixture of E/Zisomers. LCMS (m/z) 250.0 [M+H], Tr=5.07 and 5.10 min (LCMS method 1).

Step 4: Synthesis of4-((4-amino-8-(4-(2-cyanoprop-1-en-1-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile(compound 40) mixture E/Z=1/1

A mixture of compound 32a (20 mg, 0.047 mmol), compound 40b (20 mg,0.080 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039mmol) in N,N-dimethylformamide (2 mL) was heated under argon at 100° C.for 8 hours. The reaction mixture was concentrated down under reducedpressure, purified by silica gel chromatography (gradient from 50-100%ethyl acetate in iso-hexanes) and then re-purified on HPLC (preparativecolumn Phenomenex Gemini 10 micron C18, 250×21.2 mm, 10 mL/min, gradientfrom 10-100% acetonitrile in water) to afford the title compound 40 as a1:1 mixture of E/Z isomers. ¹H NMR (600 MHz, DMSO-d₆) δ 8.26 (s, 1H),7.82-7.74 (m, 2H), 7.64-7.23 (m, 7H), 2.23-2.19 (m, 3H), 1.96 (s, 6H).LCMS (m/z) 430.8 [M+H], Tr=3.86 min (LCMS method 1).

Example 41(E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzonitrile—Compound41

Step 1: Synthesis of4-((8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzonitrile(Compound 41a)

A mixture of compound 34a (260 mg, 1 mmol) and 4-aminobenzonitrile (130mg, 1.1 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated inmicrowave at 130° C. for 30 minutes. The reaction mixture was cooleddown to room temperature and diethyl ether (10 mL) was added. The solidproduct was filtered off and washed with diethyl ether (3×20 mL) toafford the title compound 41a. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (bs,1H), 9.41 (bs, 1H), 8.11 (d, J=8.8 Hz, 2H), 8.04-7.96 (m, 2H), 7.80 (d,J=8.8 Hz, 2H), 7.19 (t, J=7.8 Hz, 1H). HRMS: (ESI+) calculated forC₁₅H₁₀ON₄Br [M+H] 341.0033, found 341.0033. LCMS (m/z) 341.1 [M+H], Tr4.52 min (LCMS method 1).

Step 2: Synthesis of(E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzonitrile(Compound 41)

A mixture of compound 41a (68 mg, 0.2 mmol), compound 1c (85 mg, 0.3mmol), potassium phosphate tribasic (92 mg, 0.4 mmol) and1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (26 mg,0.04 mmol) was dissolved in N,N-dimethylformamide:water mixture (85:15,40 mL) under argon. The reaction was heated to 80° C. for 3 hours. Thereaction mixture was concentrated down under reduced pressure and theresidue was purified by silica gel chromatography (gradient from 50-80%ethyl acetate in iso-hexanes) and then repurified by HPLC reverse phasechromatography (gradient 5-100% acetonitrile in water with 0.1%trifluoroacetic acid) to afford the TFA salt of compound 41. ¹H NMR (400MHz, DMSO-d₆) δ 10.96 (bs, 1H), 9.15 (bs, 1H), 8.05 (dd, J=7.9, 1.6 Hz,1H), 7.75 (d, J=16.7 Hz, 1H), 7.57 (dd, J=7.3, 1.6 Hz, 1H), 7.53 (s,2H), 7.48-7.29 (m, 6H), 6.56 (d, J=16.7 Hz, 1H), 1.93 (s, 6H). LCMS(m/z) 418.3 [M+H], Tr=2.72 min (LCMS method 2).

Example 42 Alternative synthesis of(E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile—Compound 1b

Alternative Synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile(Compound 1b)

To a solution of diethyl cyanomethylphosphonate (266 mg, 1.5 mmol) intetrahydrofuran (10 mL) was added potassium t-butoxide (168 mg, 1.5mmol) at 0° C. with stirring for 30 minutes. After that, compound 40a(212 mg, 1 mmol) in tetrahydrofuran (10 mL) was added dropwise into thereaction mixture at room temperature and the reaction mixture wasstirred at room temperature overnight. The reaction mixture was quenchedwith water. Ethyl acetate was added and the organic layer was washedwith brine, dried over anhydrous calcium chloride and concentrated downunder reduced pressure. The residue was purified by silica gel columnchromatography (gradient from 0-20% ethyl acetate in iso-hexanes) toafford the title compound 1b. ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, J=16.6Hz, 1H), 7.12 (s, 2H), 5.84 (d, J=16.6 Hz, 1H), 2.42 (s, 6H). LCMS (m/z)no MS signal, Tr=2.78 min (LCMS method 2).

Example 43 Alternative synthesis of4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile—Compound 8a

Step 1: Synthesis of3-bromo-2-((triphenylphosphoranylidene)amino)benzonitrile (Compound 43a)

A solution of triphenylphosphine (10.65 g, 40.6 mmol) indichlormomethane (200 mL) was treated slowly with bromine (6.49 g, 40.6mmol) at 0° C. for 5 minutes. Then triethylamine (8.22 g, 81.2 mmol) wasadded followed by addition of 2-amino-3-bromobenzonitrile (4.00 g, 20.3mmol, Abblis, AB1000095). Then, the ice bath was removed and thereaction mixture was stirred at room temperature for 8 hours. Thereaction mixture was poured onto water and extracted two times withdichloromethane. The combined organics were washed with brine and driedover magnesium sulfate. Solvent was removed under reduced pressure andthe residue was subjected to silica gel chromatography (gradient from0-30% ethyl acetate in iso-hexanes) to afford the title compound 43a. ¹HNMR (400 MHz, DMSO-d₆) δ 7.80-7.70 (m, 6H), 7.66 (dt, J=7.9, 1.4 Hz,1H), 7.64-7.58 (m, 3H), 7.57-7.47 (m, 6H), 7.40 (dt, J=7.7, 1.5 Hz, 1H),6.64 (td, J=7.8, 1.5 Hz, 1H). LCMS (m/z) 457.1 [M+H], Tr=2.99 min (LCMSmethod 2).

Step 2: alternative synthesis4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile (Compound 8a)

To a solution of compound 43a (500 mg, 1.09 mmol) in2-methyltetrahydrofuran (10 mL) was added 4-isocyanatobenzonitrile (173mg, 1.20 mmol, Sigma-Aldrich) at 0° C. and the reaction mixture wasstirred at 0° C. for 30 minutes. 2M ammonia in isopropanol (3.3 mL, 6.6mmol) was added and the reaction mixture was heated to reflux for 3hours then concentrated down under reduced pressure. The residue waspurified by silica gel chromatography (gradient from 0-40% ethyl acetatein iso-hexanes) to afford the title compound 8a. ¹H NMR (400 MHz,DMSO-d₆) δ 9.74 (s, 1H), 8.35 (d, J=8.8 Hz, 2H), 8.16 (d, J=8.0 Hz, 1H),8.01 (d, J=7.5 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.16 (t, J=7.8 Hz, 1H).LCMS (m/z) 340.0 [M+H], Tr=4.06 min (LCMS method 1).

BIOLOGICAL EXAMPLES Example A High Throughput Screening of Anti-HIV-1 RT(Reverse Transcriptase)

Compounds were screened in a miniaturized, high throughput cytopathiceffect assay for activity against HIV-1 HBX2 (wild type) and HIV-1reverse transcriptase mutants K103N and Y181C. In Tables 1 and 2 below,“w.t.” refers to results of the tested compounds run with the wildtype 1and “w.t. assay 2” refers results of the tested compounds run with thewildtype on the same day as the testing of the compounds with themutants. Thus, “w.t. assay 2” was run under the same conditions as thetesting of the compounds with the mutants and provides a directcomparison with the results from the testing with the mutants.

Ten-point serial dilutions of compounds with half-log step size weregenerated in DMSO. AZT (5 M) was used as the positive control and DMSOas the negative control. The Echo acoustic dispenser was used to deliver200 nL of serially diluted compound into sterile 384 well tissue cultureassay plates. Two million MT-4 cells were incubated with each of the 3viruses at MOI of 0.0005 in separate 1 mL infection tubes for 1 hour at37° C. The cells were diluted in cell culture medium (RPMI+10% FBS) to50,000 cells/mL. The infected cells were added to 384 well assay platescontaining serially dilute compounds. Assay plates were incubated for 5days in a humidified incubator set at 37° C. and 500 CO₂. To measure thecytopathic effect of HIV, 40 μL Cell TiterGlo was added to each well andthe resulting luminescence signal is read with the Envision plate reader(Perkin Elmer). Data were normalized to positive and negative controlsin each plate and expressed as % CPE Protection. EC₅₀ values weredefined as the compound concentration that caused a 50% decrease inluminescence signal, and were calculated by non-linear regression usingPipeline Pilot software by applying a four parameter fit equation(Accelrys, San Diego, Calif.). Results are disclosed in Table 1.

TABLE 1 MT4 MT4 EC₅₀ EC₅₀ (nM) against Com- (nM) w.t. FC against poundagainst assay mutant ID w.t. 2* K103N Y181C K103N Y181C 1 3.0 6.2 8.817.8 1.4 2.9 2 3.7 3.6 4.0 10.9 1.1 3.0 3 NA 12.9 12.0 50.2 0.9 3.9 49.2 9.8 19.1 47.0 2.0 4.8 5 1.3 1.5 2.5 12.0 1.7 8.2 6 99.3 82.6 81.1469.5 1.0 5.7 7 122.2 116.8 130.5 >500 1.1 >4.3 8 2.7 2.8 3.7 21.7 1.37.8 9 3.4 3.2 3.5 10.8 1.1 3.4 10 2.8 3.0 2.9 29.3 1.0 9.8 11 4.7 4.25.2 126.4 1.2 29.8 12 1.8 1.8 1.7 12.5 0.9 6.9 13 3.2 4.3 5.9 27.4 1.46.4 14 8.1 12.7 15.1 121.9 1.2 9.6 15 22.6 33.2 72.2 179.5 2.2 5.4 166.3 7.5 12.5 42.6 1.7 5.7 17 229.1 189.9 150.8 >500 0.8 >2.6 18 21.913.1 12.1 112.3 0.9 8.6 19 27.5 29.0 30.3 79.7 1.0 2.7 20 7.0 6.6 7.169.9 1.1 10.5 21 10.1 10.6 10.8 187.0 1.0 17.6 22 69.3 87.5 101.4 >5001.2 >5.7 23 8.7 NA NA NA NA NA 24 27.8 27.8 32.5 478.5 1.2 17.2 25 39.128.3 44.1 159.8 1.6 5.6 26 2.7 2.0 2.4 27.2 1.2 13.5 27 6.3 3.8 5.3399.7 1.4 105.9 28 11.4 9.1 14.3 57.2 1.6 6.3 29 22.1 18.6 33.4 >5001.8 >26.9 30 15.9 13.0 17.0 55.6 1.3 4.3 31 10.5 8.6 17.6 432.5 2.1 50.532 1.9 1.3 1.5 10.5 1.2 8.3 33 2.1 1.5 3.2 12.3 2.1 7.9 34 2.4 3.0 3.211.3 1.0 3.7 35 12.8 16.8 16.9 38.6 1.0 2.3 36 7.7 10.5 10.1 87.3 1.08.3 37 4.7 6.8 7.8 22.1 1.2 3.3 38 6.0 7.9 7.0 18.6 0.9 2.4 39 5.9 8.912.1 27.2 1.4 3.0 40 6.8 9.9 16.3 36.1 1.7 3.7 (mixture of isomers) 416.3 9.5 15.7 32.8 1.6 3.4 *w.t. assay 2 were ran on the same day as theassays with K103N and Y181C mutants.

The high-throughput screening was also run for nevirapine (“NPV”),rilpivirine (“RPV”), and efavirenz (“EFV”). Nevirapine was obtained fromToronto Research Chemicals, Inc. (Toronto, Canada; Catalogue #N391275).Rilpivirine was obtained from Key Organics Ltd. (Camelford, Cornwall,United Kingdom; Catalogue #KE-0036). Efavirenz was obtained from TorontoResearch Chemicals, Inc. (Toronto, Canada; Catalogue E425000). Theresults are shown below in Table 2.

TABLE 2 MT4 EC₅₀ MT4 EC₅₀ (nM) (nM) against FC against Com- against w.t.mutant pound w.t. assay 2* K103N Y181C K103N Y181C Nevirapine 65.0 ND NDND ND ND (“NVP”) Rilpivirine 0.9 1.3 1.5 3.8 1.2 3.1 (“RPV”) Efavirenz1.3 1.6 46.4 3.8 28.9 2.3 (“EFV”) *w.t. assay 2 were ran on the same dayas the assays with K103N and Y181C mutants. ND: not determined

It is understood that EC₅₀ may be evaluated by techniques known in theart. In one embodiment, the compounds exhibit an EC₅₀ of less than about3000 nM in the wild-type or any of the HIV RT mutants, as measured bythe method disclosed in the “high throughput screening of anti-HIVmutants K103N and Y181C” assay section discussed above. In oneembodiment, the compounds exhibit an EC₅₀ of less than about 1000 nM,500 nM, 400 nM, 300 nM, 250 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM, 5nM, or 1 nM in the wild-type or any of the HIV RT mutants (e.g., K103N,Y181C).

Example B Resistance Profile Against HIV-1 RT (Reverse Transcriptase)Mutants

Compounds were tested for antiviral activity against a panel of NNRTIresistant viruses. A panel of 8 clonal site-directed mutant virusesrepresenting the major resistance development pathways againstrilpivirine (“RPV”), efavirenz (“EFV”), and nevirapine (“NVP”),containing both single and double mutations within HIV-1 reversetranscriptase was employed. Further details and background can be foundin Janssen et al, J. Med. Chem, 2005, 48, 1901-1909; Das et al., Proc.Nat. Acad. Sci., 2008, vol., 105, no. 5, 1466-1471; and Kuroda et al.,Nature Chemistry, 2013, DOI: 10.1038/NCHEM.1559. Retention of fullantiviral potency against the K103N mutation relative to the wild typevirus was considered especially desirable as this mutation is present ina minor subset of treatment-naïve patients (1.4%). HIV-1 recombinantstrains encoding reverse transcriptase mutations K103N, Y181C, Y188L,G190A, K103N/Y181C, L100I/Y181C, E138K or E138K/M184V were constructedby site-directed mutagenesis. Wild-type and mutant viruses were preparedby transfecting infectious proviral HXB2-based cDNA clones into MT-2cells and harvesting the cell supernatants. MT-2 cells were infectedwith wild-type and mutant HIV-1 strains at a multiplicity of infection(MOI) of 0.005 by gentle mixing for 3 hours at 37° C. and then added ata density of 16,667 cells per well in 50 μL complete RPMI cell culturemedia (containing 10% fetal bovine serum (FBS) and 10%penicillin-streptomycin) to 96-well plates containing 50 μL of a 3-foldserial dilution of test compounds in RPMI medium. After 5 days ofincubation at 37° C. in a humidified incubator in the presence of 5%CO2, 100 μL of Cell Titer-Glo™ Reagent (Promega Biosciences, Inc.,Madison, Wis.) was added to each well and the relative light units (RLU)measured on an Envision plate reader. The virus-induced cytopathiceffect was determined as a percentage of the RLU measurements fromsamples with fully suppressed virus replication after subtracting thesignal from untreated (DMSO) controls. The EC₅₀ value was defined as thecompound concentration inducing a 50% decrease in virus replication.Data analysis for the antiviral activity observed in MT-2 cells wasperformed using XL-Fit™ software (IDBS, Guildford, Surrey, UK) tocalculate EC₅₀ from an 8-point dose-response curve using the followingequation:

$y = {M - \frac{\left( {M - H} \right) \times {EC}_{50}^{n}}{\left( {{EC}_{50}^{n} + x^{n}} \right)}}$

where y=virus inhibition, x=drug concentration, M=maximum inhibition,H=minimum inhibition and n=Hill coefficient. EC₅₀ values (mean±standarddeviation) were calculated from at least three independent experimentsperformed in triplicate. The level of resistance was calculated as aratio of the mean EC₅₀ for each mutant/WT virus. Results are disclosedin FIG. 1 and in Tables 3 and 4 below.

TABLE 3 Biology resistance panel-low throughput fold change (FC) Com-L100I/ K103N/ E138K/ pound K103N Y181C Y181C Y181C Y188L G190A M184V 11.3 5.7 6.9 14.8 15.2 0.6 ND 2 0.9 4.0 1.6 4.1 10.0 1.6 5.0 3 1.0 3.41.0 3.4 13.7 ND ND 4 1.4 4.9 5.4 12.8 16.9 ND ND 5 1.6 15.4 18.9 208.0174.0 ND ND 9 1.0 5.7 4.0 14.7 11.4 ND ND 10 0.9 11.9 3.8 19.9 53.6 NDND 11 2.1 154.0 85.0 157.0 161.0 ND ND 34 1.4 3.4 1.7 12.4 18.7 ND 4.2ND: not determined

The resistance profile against HV-1 RT mutants was also run fornevirapine (“NPV”), rilpivirine (“RPV”), and efavirenz (“EFV”).Nevirapine was obtained from Toronto Research Chemicals, Inc. (Toronto,Canada; Catalogue #N391275). Rilpivirine was obtained from Key OrganicsLtd. (Camelford, Cornwall, United Kingdom; Catalogue #KE-0036).Efavirenz was obtained from Toronto Research Chemicals, Inc. (Toronto,Canada; Catalogue #E425000). The results are shown below in Table 4.

TABLE 4 Biology resistance panel-low throughput fold change (FC) Com-L100I/ K103N/ E138K/ pound K103N Y181C Y181C Y181C Y188L G190A M184VNevir- 87.0 >229 >229 ND >229 183.0 ND apine (“NVP”) Ril- 1.0 4.6 18.17.7 22.8 0.8 3.0 pivirine (“RPV”) Efa- 48.1 3.6 >200 83.5 132.5 14.8 NDvirenz (“EFV”) ND: not determined

Example C

hERG Assay

Cells:

AVIVA's CHO cell line, which stably expresses hERG channels, was usedfor the study. Cells were cultured in DMEM/F12 containing 10% FBS, 1%penicillin/streptomycin and 500 μg/ml G418. Before testing, cells wereharvested using Accumax (Innovative Cell Technologies).

Solutions:

For electrophysiological recordings, the following solutions were used:

External Solution: 2 mM CaCl₂); 2 mM MgCl₂; 4 mM KCl; 150 mM NaCl; 10 mMGlucose; 10 mM HEPES; 305-315 mOsm; pH 7.4 (adjusted with 5M NaOH.)Internal Solution: 140 mM KCl; 10 mM MgCl₂; 6 mM EGTA; 5 mM HEPES-Na; 5mM ATP-Mg; 295-305 mOsm; pH 7.25 (adjusted with 1M KOH).

Electrophysiology:

Whole cell recordings were performed using PX 7000A (Axon Instruments)with AVIVA's SealChip™ technology. Cells were voltage clamped at aholding potential of −80 mV. The hERG current was then activated by adepolarizing step to −50 mV for 300 ms. This first step at −50 mV wasused as a baseline for measuring peak amplitude of the tail current.Next, a voltage step to +20 mV was applied for 5 s to activate thechannels. Finally, a step back to −50 mV for 5 s removed activation andthe deactivating tail current was recorded.

Test Article Handling and Dilutions:

All test articles were prepared from 10 mM DMSO stock solutions.Solutions were mixed by sonication for 20 min, followed by vigorousvortexing. Prior to testing, compounds were diluted to testconcentrations in glass vials using External Solution. Dilutions wereprepared no longer than 20 min prior to use.

Electrophysiology Procedures

After achieving whole cell configuration, cells were monitored for 90 sto assess stability and then washed with External Solution for 66 s. Thevoltage protocol was then applied to the cells every 12 s throughout theprocedure. Only stable cells with recording parameters above thresholdwere allowed to enter the drug addition procedure.

External solution containing 0.1% DMSO (vehicle) was applied to thecells to establish a baseline. After allowing the current to stabilizefor 3 to 10 min, test articles were applied. Test article solutions wereadded to cells in 4 separate additions. Cells were kept in test solutionuntil effect of the test article reached steady state, to a maximum of12 min. Next, 1 μM cisapride (positive control) was added. Finally,washout with External Solution was performed until the recovery currentreached steady state.

Data Analysis

Data analysis was performed using DataXpress (Axon Instruments),Clampfit (Axon Instruments) and Origin (OriginLab Corporation) software.Results are disclosed in Table 5. The greater than values in Table 5indicate the maximum achievable concentration in the assay (e.g.,compounds achieving their solubility limit).

TABLE 5 Compound No. hERG (μM) 2 >1 9 >3 10 >3 11 >3 12 >3 13 1.3 34 >3

The hERG assay was also run for rilpivirine (“RPV”). The result was 0.5μM.

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present disclosure.

The Examples disclosed herein describe the synthesis of compoundsdisclosed herein as well as intermediates used to prepare the compounds.It is to be understood that individual steps described herein may becombined. It is also to be understood that separate batches of acompound may be combined and then carried forth in the next syntheticstep.

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure.

1-43. (canceled)
 44. A method for treating or preventing an HIVinfection in a subject comprising administering to the subject acompound of formula (I):

wherein: Q is

X¹, X², and X³ are each independently N or C(R¹¹), provided that, atmost 2 of X¹, X², and X³ are N; R¹ is —H, —CN, —OR^(a), —C(O)OR^(a),halogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or C₁₋₆heteroalkyl, wherein eachC₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionallysubstituted with 1, 2, 3, 4, or 5 R¹² groups, which may be same ordifferent; R² is —CN; R³ is —H, —OR^(a), —SR^(a), —NR^(a)R^(b),—NHC(O)NR^(a)R^(b), C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or C₁₋₆ heteroalkyl,wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl isoptionally substituted with 1, 2, 3, 4, or 5 R¹² groups, which may besame or different; R⁴ is —H or —OR^(a); R⁵ is —H, —OR^(a), halogen,—NO₂, —CN, —NR^(a)R^(b), —NHC(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),—CH₂C(O)NR^(a)R^(b), C₁₋₆alkyl, C₃₋₁₀cycloalkyl, or C₁₋₆ heteroalkyl,wherein each C₁₋₆alkyl, C₃₋₁₀cycloalkyl, and C₁₋₆ heteroalkyl isoptionally substituted with 1, 2, 3, 4, or 5 R¹² groups, which may besame or different; R⁶ is —H; R⁷ is C₁₋₆alkyl, halogen, or —OR^(a); R⁸ isC₁₋₆alkyl, halogen, or —OR^(a); R⁹ is —H, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl,wherein each C₁₋₆alkyl and C₃₋₁₀cycloalkyl is optionally substitutedwith 1, 2, 3, 4, or 5 R¹² groups, which may be same or different; R¹⁰ is—H, C₁₋₆alkyl, or C₃₋₁₀cycloalkyl, wherein each C₁₋₆alkyl andC₃₋₁₀cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5 R¹²groups, which may be same or different; each R¹¹ is independently —H,—CN, —OR^(a), —C(O)OR^(a), halogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, orC₁₋₆heteroalkyl, which may be same or different, wherein each C₁₋₆alkyl,C₃₋₁₀cycloalkyl, and C₁₋₆heteroalkyl is optionally substituted with 1,2, 3, 4, or 5 R¹² groups, which may be same or different; each R¹² isindependently C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 5-10 memberedheterocyclyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, halogen, —OR^(a),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b), —OC(O)NR^(a)R^(b),—N^(a)C(O)OR^(b), —SR^(a), —S(O)₁₋₂R^(a), —S(O)₂F, —S(O)₂NR^(a)R^(b),—NR^(a)S(O)₂R^(b), —N₃, —CN, or —NO₂; wherein each C₁₋₆alkyl,C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, and 5-10 membered heterocyclyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents selected fromhalogen, —OR^(a), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(a)R^(b),—OC(O)NR^(a)R^(b), —NR^(a)C(O)OR^(b), —SR^(a)—S(O)₁₋₂R^(a), —S(O)₂F,—S(O)₂NR^(a)R^(b), —NR^(a)S(O)₂R^(b), —N₃, —CN, and —NO₂, groups, whichmay be same or different; each R^(a) and R^(b) is independently —H,—NH₂, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 5-10 memberedheterocyclyl, C₆₋₁₀aryl, or 5-10 membered heteroaryl, wherein eachC₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, 5-10 membered heterocyclyl,C₆₋₁₀aryl, and 5-10 membered heteroaryl is optionally substituted with1, 2, 3, 4, or 5 R¹³ groups, which may be same or different; or R^(a)and R^(b) together with the atoms to which they are attached form a 5-10membered heterocycle; and each R¹³ is independently —CN, halogen,C₁₋₆alkyl, C₃₋₁₀cycloalkyl, C₁₋₆heteroalkyl, or 5-10 memberedheterocyclyl, or a tautomer or a pharmaceutically acceptable saltthereof; in combination with one, two, three, or four additionaltherapeutic agents independently selected from raltegravir, Truvada®(tenofovir disoproxil fumarate+emtricitabine, TDF+FTC), maraviroc,enfuvirtide, Epzicom® (Livexa®, abacavir sulfate+lamivudine, ABC+3TC),Trizivir® (abacavir sulfate+zidovudine+lamivudine, ABC+AZT+3TC),adefovir, adefovir dipivoxil, Stribild®(elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine),rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®,rilpivirine+tenofovir disoproxil fumarate+emtricitabine), Cobicistat,Atripla® (efavirenz+tenofovir disoproxil fumarate+emtricitabine),atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, Aluvia®(Kaletra®, lopinavir+ritonavir), ritonavir, emtricitabine, atazanavirsulfate+ritonavir, darunavir, lamivudine, Prolastin, fosamprenavir,fosamprenavir calcium, efavirenz, Combivir® (zidovudine+lamivudine,AZT+3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon,didanosine, stavudine, indinavir, indinavir sulfate,tenofovir+lamivudine, zidovudine, nevirapine, saquinavir, saquinavirmesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, delavirdine,delavirdine mesylate, Radha-108 (Receptol), Hlviral,lamivudine+tenofovir disoproxil fumarate, efavirenz+lamivudine+tenofovirdisoproxil fumarate, phosphazid, lamivudine+nevirapine+zidovudine,abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovirdisoproxil fumarate, tenofovir alafenamide, tenofovir alafenamidefumarate, and tenofovir alafenamide hemifumarate. 45-51. (canceled) 52.The method of claim 44, wherein one of the additional therapeutic agentsis selected from tenofovir alafenamide, tenofovir alafenamide fumarate,and tenofovir alafenamide hemifumarate.
 53. The method of claim 44,wherein Q is


54. The method of claim 44, wherein X¹, X², and X³ are each CH.
 55. Themethod of claim 44, wherein X¹, X², and X³ are C(R¹¹); each R¹¹ areindependently selected from —H, —CN, —OR^(a), halogen, and C₁₋₆alkyl;and R¹ is selected from —H, —CN, —OR^(a), halogen, and C₁₋₆alkyl. 56.The method of claim 44, wherein R³ is —H, —OR^(a), —NR^(a)R^(b),—NHC(O)NR^(a)R^(b), C₁₋₆alkyl, or C₁₋₆ heteroalkyl.
 57. The method ofclaim 44, wherein R³ is —NH₂ or —OH.
 58. The method of claim 44, whereinR⁴ is —H, and R⁵ is —H, —OR^(a), halogen, —NO₂, —CN, —NR^(a)R^(b),—NHC(O)NR^(a)R^(b), or C₁₋₆alkyl.
 59. The method of claim 44, whereinR⁴, R⁵, and R⁶ are —H.
 60. The method of claim 44, wherein R⁷ isC₁₋₆alkyl.
 61. The method of claim 44, wherein R⁸ is C₁₋₆alkyl.
 62. Themethod of claim 44, wherein R⁷ and R⁸ are C₁₋₆alkyl.
 63. The method ofclaim 44, wherein R⁷ and R⁸ are methyl.
 64. The method of claim 44,wherein R⁹ is —H or C₁₋₆alkyl.
 65. The method of claim 44, wherein R¹⁰is —H or C₁₋₆alkyl.
 66. The method of claim 44, wherein Q is


67. The method of claim 44, wherein the compound of formula (I), or atautomer or a pharmaceutically acceptable salt thereof, is a compound offormula:

or a tautomer or a pharmaceutically acceptable salt thereof.